G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Thrombin is a serine protease with a central role in blood clotting.It cleaves various substrates involved in coagulation, and activates cellsurface receptors via a novel proteolytic action. Thrombin stimulatesaggregation and secretion in blood platelets at the site of vascular injury,and also has inflammatory and reparative actions, stimulating chemotaxis inmonocytes, proliferation of fibroblasts and lymphocytes, and inducingendothelium-dependent relaxation of blood vessels. The protein activatesa number of substrates involved in coagulation: it cleaves fibrinogen tofibrin and activates coagulation factor XIII; it also activates factors Vand VIII. When bound to thrombomodulin, it activates plasma protein C,which, in concert with protein S, inactivates factors Va and VIIIa, leadingto a decrease in thrombin formation.The thrombin receptor is expressed in high levels in platelets, vascularendothelial cells, and various cell lines. The receptor activatesphosphoinositide metabolism via a pertussis-toxin-insensitive G-protein,and inhibits adenylyl cyclase via a pertussis-toxin-sensitive G-protein.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range offunctions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Neuropeptide receptors are present in very small quantities in the celland are embedded tightly in the plasma membrane. The neuropeptides exhibita high degree of functional diversity through both regulation of peptideproduction and through peptide-receptor interaction []. The mammaliantachykinin system consists of 3 distinct peptides: substance P, substanceK and neuromedin K. All possess a common spectrum of biological activities,including sensory transmission in the nervous system and contraction/relaxation of peripheral smooth muscles, and each interacts with aspecific receptor type.In the periphery, NK2 receptors are found in smooth muscle of therespiratory, gastrointestinal and urogenital systems. NK2 receptorsactivate the phosphoinositide pathway through a pertussis-toxin-insensitiveG-protein, probably of the Gq/G11 class.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists ofapproximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents the chemoreceptor Srd [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.Srh is part of the Str superfamily of chemoreceptors [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class b (Srb) from the Sra superfamily []. Srb receptors contain 6-8 hydrophobic, putative transmembrane, regions and can be distinguished from other 7TM GPCR receptors by their own characteristic TM signatures.Srbc is a solo family amongst the superfamilies of chemoreceptors.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents Sri, which is part of the Str superfamily of chemoreceptors.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class r (Str) from the Str superfamily [, ]. Almost a quarter (22.5%) of str and srj family genes and pseudogenes in C. elegans appear to have been newly formed by gene duplications since the species split [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class v (Srv) from the Srg superfamily [, ]. Srg receptors contain seven hydrophobic, putative transmembrane, regions and can be distinguished from other 7TM GPCR receptors by their own characteristic TM signatures.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class j (Srj) from the Str superfamily [, ]. The Srj family is designated as the out-group based on its location in preliminary phylogenetic analyses of the entire superfamily [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.Srab is part of the Sra superfamily of chemoreceptors. The expression pattern of the srab genes is biologically intriguing. Of the six promoters successfully expressed in transgenic organisms, one was exclusively expressed in the tail phasmid neurons, two were exclusively expressed in a head amphid neuron, and two were expressed both in the head and tail neurons as well as a limited number of other cells [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents a domain found in serpentine receptor class x (Srx) from the Srg superfamily [, ]. Srg receptors contain seven hydrophobic, putative transmembrane, regions and can be distinguished from other 7TM GPCR receptors by their own characteristic TM signatures.
Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) []. These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome []. Once PA is attached to the host receptor [], it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation [, ]. EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling [].This entry represents a central domain in the edema factor adenylyl cyclase protein of anthrax toxin, as well as in adenylyl cylcases from other bacterial toxins.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class xa (Srxa), from the Str superfamily [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Neuromedin U is a neuropeptide, first isolated from porcine spinal cord andexpressed widely in the gastrointestinal, genitourinary and central nervoussystems []. Neuromedin U has potent contractile activity on smooth muscle and this activity is believed to reside within the C-terminal portion of the peptide, which is highly conserved between species. Other roles for the peptide include: regulation of blood flow and ion transport in the intestine, regulation of adrenocortical function and increased bloodpressure []. The roles of neuromedin U in the central nervous systemare poorly understood, but may include: regulation of food intake,neuroendocrine control, modulation of dopamine actions and involvement inneuropsychiatric disorders. Two G protein-coupled receptor subtypes,with differing expression patterns, have been identified and shown to bindneuromedin U.The neuromedin U type 2 receptor (NMU2) is expressed most abundantly in thecentral nervous system, particularly in the medulla oblongata, pontinereticular formation, substantia nigra, spinal cord and thalamus []. High levels of expression have also been found in the thymus, thyroid and testes[]. NMU2 has been detected at much lower levels in some peripheral tissues, including the kidney, lung, trachea and gastrointestinal tract.
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-4 subunit is predominantly expressed in neuronal tissue, althoughthere is some evidence for expression in lung and prostate [, ]. Themodulatory properties of the subunit have been investigated usingheterologous expression systems. Coexpression of the VDCGG-4 subunit with P/Q-type channels shifts the steady-state inactivation curve of these channels to more hyperpolarised potentials [, ].
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-1 subunit is a 25kDa protein expressed exclusively in skeletal muscle cells, where it functions as a dihydropyridine-sensitive, L-type calcium channel subunit []. The modulatory properties of VDCCG-1 subunits have been investigated using heterologous expression systems. Coexpressionof VDCCG-1 subunits with L-type or P/Q-type channels induces moderate changes in activation and inactivation properties, and modification of thepeak current amplitude of these channels [, ].
Carbamoyl phosphate synthase (CPSase) is a heterodimeric enzyme composed of a small and a large subunit (with the exception of CPSase III, see below). CPSase catalyses the synthesis of carbamoyl phosphate from biocarbonate, ATP and glutamine () or ammonia (), and represents the first committed step in pyrimidine and arginine biosynthesis in prokaryotes and eukaryotes, and in the urea cycle in most terrestrial vertebrates [, ]. CPSase has three active sites, one in the small subunit and two in the large subunit. The small subunit contains the glutamine binding site and catalyses the hydrolysis of glutamine to glutamate and ammonia. The large subunit has two homologous carboxy phosphate domains, both of which have ATP-binding sites; however, the N-terminal carboxy phosphate domain catalyses the phosphorylation of biocarbonate, while the C-terminal domain catalyses the phosphorylation of the carbamate intermediate []. The carboxy phosphate domain found duplicated in the large subunit of CPSase is also present as a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase () (ACC), propionyl-CoA carboxylase () (PCCase), pyruvate carboxylase () (PC) and urea carboxylase ().Most prokaryotes carry one form of CPSase that participates in both arginine and pyrimidine biosynthesis, however certain bacteria can have separate forms. The large subunit in bacterial CPSase has four structural domains: the carboxy phosphate domain 1, the oligomerisation domain, the carbamoyl phosphate domain 2 and the allosteric domain []. CPSase heterodimers from Escherichia coli contain two molecular tunnels: an ammonia tunnel and a carbamate tunnel. These inter-domain tunnels connect the three distinct active sites, and function as conduits for the transport of unstable reaction intermediates (ammonia and carbamate) between successive active sites []. The catalytic mechanism of CPSase involves the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain.Eukaryotes have two distinct forms of CPSase: a mitochondrial enzyme (CPSase I) that participates in both arginine biosynthesis and the urea cycle; and a cytosolic enzyme (CPSase II) involved in pyrimidine biosynthesis. CPSase II occurs as part of a multi-enzyme complex along with aspartate transcarbamoylase and dihydroorotase; this complex is referred to as the CAD protein []. The hepatic expression of CPSase is transcriptionally regulated by glucocorticoids and/or cAMP []. There is a third form of the enzyme, CPSase III, found in fish, which uses glutamine as a nitrogen source instead of ammonia []. CPSase III is closely related to CPSase I, and is composed of a single polypeptide that may have arisen from gene fusion of the glutaminase and synthetase domains []. This entry represents the CPSase domain of the large subunit of carbamoyl phosphate synthase.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].In the absence of cAMP, Protein Kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits []. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. All R subunits have a conserved domain structure consisting of the N-terminal dimerization domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.Two types of regulatory (R) subunits exist - types I and II - which differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II were further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. This entry represents the dimerization-anchoring domain of types I-alpha, I-beta, II-alpha and II-beta regulatory subunits of PKA proteins.The dimerization-anchoring domain is located within the first 45 residues of each regulatory subunit, and forms a high affinity binding site for A-kinase-anchoring proteins (AKAPs) [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity insequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligandsuch as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Calcitonin gene-related peptide (CGRP) type 1 receptor (also known as Calcitonin receptor-like receptor) is a neuropeptide with diversebiological effects including potent vasodilator activity [, ]. Messenger RNA for this receptor is predominantly expressed in the lung and heart, with specific localisation to lung alveolar cells and cardiac myocytes []. Mutations in the gene for this protein has been related to pontaneous miscarriage and subfertility []. In the rat lung, it is associated with blood vessels; the gene may therefore play an important role in the maintenance of vascular tone []. mRNA is also found in the cerebellum []. The ligand for this receptor-like protein remains to be discovered.
Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) []. These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome []. Once PA is attached to the host receptor [], it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation [, ]. EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling [].This entry represents the central domain found in the lethal factor protein of anthrax toxin.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length []. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors [, , , ]. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.This entry represents three conserved sites found in family 3 GPCR receptor proteins. The first conserved site is centred around a highly conserved hydrophobic segment in the central part of the N-terminal extracellular region; the second conserved site is centred around a cluster of six cysteines in the C-terminal part of the extracellular domain; the third conserved site is centred around the C-terminal part of the cytoplasmic loop between the fifth and sixth transmembrane domains.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. This entry represents a pair of conserved sites found within family 2 GPCR receptor proteins. The first conserved site spans three of the five highly conserved cysteine residues found within the N-terminal extracellular domain that may be involved in disulphide bonds. The second conserved site within a region spanning the C-terminal part of the last transmembrane region and the beginning of the adjacent intracellular region.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Neuropeptide receptors are present in very small quantities in the celland are embedded tightly in the plasma membrane. The neuropeptides exhibita high degree of functional diversity through both regulation of peptideproduction and through peptide-receptor interaction []. The mammaliantachykinin system consists of 3 distinct peptides: substance P, substanceK and neuromedin K. All possess a common spectrum of biological activities,including sensory transmission in the nervous system and contraction/relaxation of peripheral smooth muscles, and each interacts with aspecific receptor type.NK3 receptors are distributed widely throughout the rat CNS, and are foundin high levels in cerebral cortex, basal ganglia and dorsal horn of thespinal chord. They have limited distribution in peripheral tissues, andare found in ganglia (e.g., myenteric plexus), kidney, and in a limitednumber of smooth muscles (e.g., rat portal vein). NK3 receptorsactivate the phosphoinositide pathway through a pertussis-toxin-insensitiveG-protein, probably of the Gq/G11 class.
Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) []. These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome []. Once PA is attached to the host receptor [], it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation [, ]. EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling [].This entry represents a central domain superfamily in the edema factor adenylyl cyclase protein of anthrax toxin, as well as in adenylyl cylcases from other bacterial toxins.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli []. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' []. Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr [, , ]. Many of these proteins have homologues in Caenorhabditis briggsae.This entry represents serpentine receptor class u (Sru) from the Srg superfamily [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (ClassB, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Vasopressin and oxytocin are members of the neurohypophyseal hormone familyfound in all mammalian species. They are present in high levels in theposterior pituitary. Vasopressin has an essential role in the control ofthe water content of the body, acting in the kidney to increase water andsodium absorption. In higher concentrations, vasopressin stimulatescontraction of vascular smooth muscle, stimulates glycogen breakdown in theliver, induces platelet activation, and evokes release of corticotrophinfrom the anterior pituitary. Vasopressin and its analogues are usedclinically to treat diabetes insipidus.In the periphery, the V1A receptor is found in high levels in vascularsmooth muscle, myometrium and the bladder where it mediates contraction.In the CNS, V1 sites are distributed widely and are found in lateral septalnucleus, hippocampus, superior collicular, substantia nigra and centralgrey matter. The receptors activate phosphoinositide metabolism througha pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.EP4 receptors are found in high levels in the intestine, and in lowerlevels in the lung, kidney, thymus, uterus and brain; they are not found inthe liver, heart, retina or in skeletal muscle. The receptors activateadenylate cyclase.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a widevariety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of theinteraction of platelets with the vascular endothelium. To date, evidencefor at least 5 classes of prostanoid receptor has been obtained. However,identification of subtypes and their distribution is hampered by expressionof more than one receptor within a tissue, coupled with poor selectivity ofavailable agonists and antagonists. Moreover, many endogenous prostanoidsundergo rapid metabolism, especially TXA2.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors,all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones and beta-endorphin are peptide products of pituitary pro-opiomelanocortin. ACTHregulates synthesis and release of glucocorticoids and aldosterone inthe adrenal cortex; it also has a trophic action on these cells.ACTH and beta-endorphin are synthesised and released in response tocorticotrophin-releasing factor at times of stress (heat, cold, infections,etc.) - their release leads to increased metabolism and analgesia.The ACTH receptor is found in high levels in the adrenal cortex - bindingsites are present in lower levels in the CNS.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].The term opioid refers to a class of substance that produces its effectsvia the major classes of opioid receptor, termed mu, delta and kappa.The receptors are found in the CNS and certain smooth muscles: mu-opioidreceptors are believed to mediate analgesia, hypothermia, respiratorydepression, miosis, bradycardia, nausea, euphoria and physical dependence,beta-endorphin being the most potent endogenous ligand; delta-receptorsmediate analgesia; and kappa-opioid receptors are believed to mediateanalgesia, sedation, miosis and diuresis, dynorphin being the most potentendogenous ligand.The X-receptor is closely related to opioid receptors, on grounds of bothsequence and function, although it is not a typical opioid receptor [].X-receptors are found in many regions of the brain and spinal cord,particularly limbic and hypothalamic structures. They are believed torepresent a new class of opioid receptors, with a potential role inmodulating various brain functions, including instinctive behaviours andemotions [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].In addition to their role in energy metabolism, purines (especiallyadenosine and adenine nucleotides) produce a wide range of pharmacologicaleffects mediated by activation of cell surface receptors. Distinctreceptors exist for adenosine. In the periphery, the main effects ofadenosine include vasodilation, bronchoconstriction, immunosuppresion,inhibition of platelet aggregation, cardiac depression, stimulation ofnociceptive afferents, inhibition of neurotransmitter release andinhibition of the release of other factors, e.g. hormones. In the CNS,adenosine exerts a pre- and post-synaptic depressant action, reducing motoractivity, depressing respiration, inducing sleep and relieving anxiety. Thephysiological role of adenosine is thought to be to adjust energy demandsin line with oxygen supply. Many of the clinical actions of methylxanthinesare thought to be mediated through antagonism of adenosine receptors. Foursubtypes of receptor have been identified, designated A1, A2A, A2B and A3.A2B receptors are widespread in the human brain relative to A2A receptors.By contrast, however, in the rat its mRNA is found only in low levels inthe brain and it has a unique distribution in the periphery, high levelsoccurring in the intestine and bladder. The receptor stimulates cAMPthrough G proteins.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partlythrough an unusual proteolytically activated GPCR []. Gene knockout experiments have provided definitive evidence for a second thrombin receptorin mouse platelets and have suggested tissue-specific roles for differentthrombin receptors. Because the physiological agonist at the receptor wasoriginally unknown, it was provisionally named protease-activated receptor(PAR) []. At least 4 PAR subtypes have now been characterised. Thus, the thrombin and PAR receptors constitute a fledgling receptor family that shares a novel proteolytic activation mechanism [].The human thrombin receptor, designated protease-activated receptor 4 (PAR4),has been cloned and characterised []. Northern blot analysis showed that PAR4 mRNA was expressed in a number of tissues, high levels being presentin lung, pancreas, thyroid, testis and small intestine. Using fluorescence in situ hybridisation, the human PAR4 gene has been mapped to chromosome 19p12 [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partlythrough an unusual proteolytically activated GPCR []. Gene knockout experiments have provided definitive evidence for a second thrombin receptorin mouse platelets and have suggested tissue-specific roles for differentthrombin receptors. Because the physiological agonist at the receptor wasoriginally unknown, it was provisionally named protease-activated receptor(PAR) []. At least 4 PAR subtypes have now been characterised. Thus, the thrombin and PAR receptors constitute a fledgling receptor family that shares a novel proteolytic activation mechanism [].The human thrombin receptor, designated protease-activated receptor 3 (PAR3),has been cloned and characterised []. PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, including human bone marrow and mouse megakaryocytes, making it a candidate for the sought-after second platelet thrombin receptor. PAR3 provides a new tool for understanding thrombin signalling and a possible target for therapeutics designed selectively to block thrombotic, inflammatory andproliferative responses to thrombin.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].In addition to their role in energy metabolism, purines (especiallyadenosine and adenine nucleotides) produce a wide range of pharmacologicaleffects mediated by activation of cell surface receptors. Distinctreceptors exist for adenosine. In the periphery, the main effects ofadenosine include vasodilation, bronchoconstriction, immunosuppresion,inhibition of platelet aggregation, cardiac depression, stimulation ofnociceptive afferents, inhibition of neurotransmitter release andinhibition of the release of other factors, e.g. hormones. In the CNS,adenosine exerts a pre- and post-synaptic depressant action, reducing motoractivity, depressing respiration, inducing sleep and relieving anxiety. Thephysiological role of adenosine is thought to be to adjust energy demandsin line with oxygen supply. Many of the clinical actions of methylxanthinesare thought to be mediated through antagonism of adenosine receptors. Foursubtypes of receptor have been identified, designated A1, A2A, A2B and A3.A2A receptors have a limited distribution in the brain and are found in thestriatum, olfactory tubercle and nucleus accumbens. In the periphery, A2receptors mediate vasodilation, immunosuppression, inhibition of plateletaggregation and gluconeogenesis. The receptors activate adenylyl cyclase through G proteins.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Bombesins are peptide neurotransmitters whose biological activity residesin a common C-terminal sequence, WAXGHXM. In the periphery, bombesin-related peptides stimulate smooth muscle and glandular secretion. In thebrain, these peptides are believed to play a role in homeostasis, thermoregulation and metabolism, and have been reported to elicit analgesia andexcessive grooming, together with central regulation of a variety ofperipheral effects.Mammalian bombesins are encoded by 2 genes. The preproGRP gene transcriptencodes a precursor of 147 amino acids, which gives GRP and GRP18-27. ThepreproNMB gene transcript encodes a precursor of 117 amino acids, which ismetabolised to neuromedin B. Receptors for these peptides have widespreaddistribution in peripheral tissue. High levels are found in smooth muscleand in the brain.The neuromedin B receptor has been characterised in rat oesophagus and raturinary bladder. It is widespread in the CNS, and is found in highlevels in olfactory nucleus and thalamic regions, and in lower levels inthe frontal cortex, dendate gyrus, amygdala and dorsal raphe. Thereceptor activates the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) []. These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome []. Once PA is attached to the host receptor [], it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation [, ]. EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling [].This entry represents a C-terminal region in the edema factor, the calmodulin-activated adenylate cyclase component of anthrax toxin, as well as in adenylyl cyclases from other bacterial toxins. The C-terminal region contains the calmodulin-dependent activation domain and the catalytic site [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Bombesins are peptide neurotransmitters whose biological activity residesin a common C-terminal sequence, WAXGHXM. In the periphery, bombesin-related peptides stimulate smooth muscle and glandular secretion. In thebrain, these peptides are believed to play a role in homeostasis, thermo-regulation and metabolism, and have been reported to elicit analgesia andexcessive grooming, together with central regulation of a variety ofperipheral effects.Mammalian bombesins are encoded by 2 genes. The preproGRP gene transcriptencodes a precursor of 147 amino acids, which gives GRP and GRP18-27. ThepreproNMB gene transcript encodes a precursor of 117 amino acids, which ismetabolised to neuromedin B. Receptors for these peptides have widespreaddistribution in peripheral tissue. High levels are found in smooth muscleand in the brain.The recently-identified BRS-3 bombesin receptor subtype is found in germcells in testis and in uteri of pregnant animals; it is also present in avariety of lung carcinoma cell lines. The receptor is believed to playa role in sperm cell division and maturation. Its action is mediated byassociation with G-proteins that activate a phosphatidylinositol-calciumsecond messenger system.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Bombesins are peptide neurotransmitters whose biological activity residesin a common C-terminal sequence, WAXGHXM. In the periphery, bombesin-related peptides stimulate smooth muscle and glandular secretion. In thebrain, these peptides are believed to play a role in homeostasis, thermoregulation and metabolism, and have been reported to elicit analgesia andexcessive grooming, together with central regulation of a variety ofperipheral effects.Mammalian bombesins are encoded by 2 genes. The preproGRP gene transcriptencodes a precursor of 147 amino acids, which gives GRP and GRP18-27. ThepreproNMB gene transcript encodes a precursor of 117 amino acids, which ismetabolised to neuromedin B. Receptors for these peptides have widespreaddistribution in peripheral tissue. High levels are found in smooth muscleand in the brain.The gastrin-releasing peptide receptor has a wide distribution in peripheraltissue. High levels are found in smooth muscle (e.g., intestine, stomachand bladder) and in secretory glands (e.g., pancreas). In the brain, it isfound in high levels in the hypothalamus, and is present in other areas inlower levels (e.g., the olfactory tract, dendate gyrus and cortex). Itis also found in various cell lines (e.g., Swiss 3T3 fibroblasts and small-cell lung carcinomas). GRP receptors activate the phosphoinositidepathway via a pertussis-toxin-insensitive G-protein, probably of the Gq/G11class.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans andmice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. This domain is found in the extracellular part of some of the secretin-like (family 2) GPCRs including the calcitonin receptor; corticotropin releasing factor receptor 1; diuretic hormone receptor; glucagon-like peptide 1 receptor; and parathyroid hormone peptide receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length []. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors [, , , ]. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.This entry represents a conserved sequence, found in the extracellular region, that contains several highly-conserved Cys residues that are predicted to form disulphide bridges.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Melanin-concentrating hormone (MCH) is a cyclic peptide originallyidentified in teleost fish []. In fish, MCH is released from thepituitary and causes lightening of skin pigment cells through pigmentaggregation. In mammals, MCH is predominantly expressed in thehypothalamus, and functions as a neurotransmitter in the control of a rangeof functions. A major role of MCH is thought to be in the regulation offeeding: injection of MCH into rat brains stimulates feeding; expression ofMCH is upregulated in the hypothalamus of obese and fasting mice; and micelacking MCH are lean and eat less. MCH and alpha melanocyte-stimulatinghormone (alpha-MSH) have antagonistic effects on a number of physiologicalfunctions. Alpha-MSH darkens pigmentation in fish and reduces feeding inmammals, whereasMCH increases feeding [].Two G protein-coupled receptors, MCH1 and MCH2, have recently beenidentified as receptors for the melanin-concentrating hormone.
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-5 subunit was identified by genomic database searching, pursuingsequences similar to VDCCG-1 and -2. Mouse, human and rat isoforms havebeen cloned. VDCCG-5 is expressed in a range of tissues, including brain,kidney and testis [].
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calciumchannel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-6 subunit was identified by high throughput genomic sequencedatabase searching, pursuing sequences similar to VDCCG-1 to -5 [].Mouse, human and rat isoforms have been cloned. VDCCG-6 is expressed in arange of tissues including brain, kidney, lung, skeletal muscle, prostateand testis [].
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-7 subunit was identified by high throughput genomic sequencedatabase searching, pursuing sequences similar to VDCCG-1 to -5.Mouse and human isofroms have been cloned. VDCCG-7 is expressed in a rangeof tissues including brain, kidney, liver, small intestine and testis [].
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classifiedas T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-8 subunit was identified by high throughput genomic sequencedatabase searching, pursuing sequences similar to VDCCG-1 to -5 [].Mouse and rat isoforms have been cloned. VDCCG-8 mRNA is expressed in thebrain and testis.
Carbamoyl phosphate synthase (CPSase) is a heterodimeric enzyme composed of a small and a large subunit (with the exception of CPSase III, see below). CPSase catalyses the synthesis of carbamoyl phosphate from biocarbonate, ATP and glutamine () or ammonia (), and represents the first committed step in pyrimidine and arginine biosynthesis in prokaryotes and eukaryotes, and in the urea cycle in most terrestrial vertebrates [, ]. CPSase has three active sites, one in the small subunit and two in the large subunit. The small subunit contains the glutamine binding site and catalyses the hydrolysis of glutamine to glutamate and ammonia. The large subunit has two homologous carboxy phosphate domains, both of which have ATP-binding sites; however, the N-terminal carboxy phosphate domain catalyses the phosphorylation of biocarbonate, while the C-terminal domain catalyses the phosphorylation of the carbamate intermediate []. The carboxy phosphate domain found duplicated in the large subunit of CPSase is also present as a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase () (ACC), propionyl-CoA carboxylase () (PCCase), pyruvate carboxylase () (PC) and urea carboxylase ().Most prokaryotes carry one form of CPSase that participates in both arginine and pyrimidine biosynthesis, however certain bacteria can have separate forms. The large subunit in bacterial CPSase has four structural domains: the carboxy phosphate domain 1, the oligomerisation domain, the carbamoyl phosphate domain 2 and the allosteric domain []. CPSase heterodimers from Escherichia coli contain two molecular tunnels: an ammonia tunnel and a carbamate tunnel. These inter-domain tunnels connect the three distinct active sites, and function as conduits for the transport of unstable reaction intermediates (ammonia and carbamate) between successive active sites []. The catalytic mechanism of CPSase involves the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain.Eukaryotes have two distinct forms of CPSase: a mitochondrial enzyme (CPSase I) that participates in both arginine biosynthesis and the urea cycle; and a cytosolic enzyme (CPSase II) involved in pyrimidine biosynthesis. CPSase II occurs as part of a multi-enzyme complex along with aspartate transcarbamoylase and dihydroorotase; this complex is referred to as the CAD protein []. The hepatic expression of CPSase is transcriptionally regulated by glucocorticoids and/or cAMP []. There is a third form of the enzyme, CPSase III, found in fish, which uses glutamine as a nitrogen source instead of ammonia []. CPSase III is closely related to CPSase I, and is composed of a single polypeptide that may have arisen from gene fusion of the glutaminase and synthetase domains []. This entry represents glutamine-dependent CPSase () from prokaryotes and eukaryotes (CPSase II).
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis []. They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage, inflammation and colitis []. A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P [].LPA is found in all cell types in small quantities (associated with membranebiosynthesis) but is produced in significant quantities by some cellularsources, accounting for the levels of LPA in serum. LPA is also found inelevated levels in ovarian cancer ascites, and acts to stimulate proliferation and promote survival of the cancer cells []. The effects of LPA on the proliferation and morphology of a number of other cell types have been well documented [, ]. However, identification of the mechanisms by which these effects are accomplished has been complicated by a number of factors, such as: a lack of antagonists, difficulty in ligand-binding experiments and the responsiveness of many cell types to LPA []. The G protein-coupled receptors EDG-2, EDG-4 and EDG-7 have now been identifiedas high affinity receptors for LPA. It has been suggested that these receptors should now be referred to as lpA1, lpA2 and lpA3 respectively [, ].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis []. They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage, inflammation and colitis []. A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P [].LPA is found in all cell types in small quantities (associated with membranebiosynthesis) but is produced in significant quantities by some cellularsources, accounting for the levels of LPA in serum. LPA is also found inelevated levels in ovarian cancer ascites, and acts to stimulate proliferation and promote survival of the cancer cells []. The effects of LPA on the proliferation and morphology of a number of other cell types have been well documented [, ]. However, identification of the mechanisms by which these effects are accomplished has been complicated by a number of factors, such as: a lack of antagonists, difficulty in ligand-binding experiments and the responsiveness of many cell types to LPA []. The G protein-coupled receptors EDG-2, EDG-4 and EDG-7 have now been identifiedas high affinity receptors for LPA. It has been suggested that these receptors should now be referred to as lpA1, lpA2 and lpA3 respectively [, ].EDG-4 is expressed at high levels in the testis and peripheral bloodleukocytes of humans, and the testis, kidney and embryonic brain in mouse.Lower levels of expression are found in human pancreas, spleen, thymus andprostate, and mouse heart, lung, spleen, thymus, stomach and brain []. Variant forms of the receptor are also expressed in cancer cells []. Binding of LPA to EDG-4 results in increased calcium levels, inhibition of adenyly cylase, activation of MAP kinases and cell rounding, through coupling to Gi/o, Gq/11 and G12/13 proteins [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis []. They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage,inflammation and colitis []. A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P [].LPA is found in all cell types in small quantities (associated with membranebiosynthesis) but is produced in significant quantities by some cellularsources, accounting for the levels of LPA in serum. LPA is also found inelevated levels in ovarian cancer ascites, and acts to stimulate proliferation and promote survival of the cancer cells []. The effects of LPA on the proliferation and morphology of a number of other cell types have been well documented [, ]. However, identification of the mechanisms by which these effects are accomplished has been complicated by a number of factors, such as: a lack of antagonists, difficulty in ligand-binding experiments and the responsiveness of many cell types to LPA []. The G protein-coupled receptors EDG-2, EDG-4 and EDG-7 have now been identifiedas high affinity receptors for LPA. It has been suggested that these receptors should now be referred to as lpA1, lpA2 and lpA3 respectively [, ].EDG-2 was originally identified as a gene involved in neuron production fromembryonic cerebral cortex []. EDG-2 is widely distributed, with highest levels in the brain (in which expression correlates with development ofoligodendrocytes and Schwann cells) []. In the periphery, EDG-2 is found in many tissues, including the heart, kidney, testis, spleen and muscle in both humans and mouse []. The receptor is also expressed in a number of cancers []. Upon binding of LPA, EDG-2 couples to G proteins of the Gi, Gq and G12/13 classes, to mediate a range of effects including: inhibition of adenylyl cyclase; activation of phospholipase C, serum response element and MAP kinases; and actomyosin stimulation. These processes lead to cell rounding and proliferation [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis []. They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage, inflammation and colitis []. A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P [].S1P is released from activated platelets and is also produced by a number of other cell types in response to growth factors and cytokines []. It is proposed to act both as an extracellular mediator and as an intracellularsecond messenger. The cellular effects of S1P include growth related effects, such as proliferation, differentiation, cell survival and apoptosis, and cytoskeletal effects, such as chemotaxis, aggregation, adhesion, morphological change and secretion. The molecule has been implicated in control of angiogenesis, inflammation, heart-rate and tumour progression, and may play an important role in a number of disease states, such as atherosclerosis, and breast and ovarian cancer []. Recently, 5 G protein-coupled receptors have been identified that act as high affinity receptors for S1P, and also as low affinity receptors for the related lysophospholipid, SPC []. EDG-1, EDG-3, EDG-5 and EDG-8 share a high degree of similarity, and are also referred to as lpB1, lpB3, lpB2 and lpB4, respectively. EDG-6 is referred to as lpC1, reflecting its more distant relationship to the other S1P receptors.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis []. They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage, inflammation and colitis []. A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P [].S1P is released from activated platelets and is also produced by a number of other cell types in response to growth factors and cytokines []. It is proposed to act both as an extracellular mediator and as an intracellularsecond messenger. The cellular effects of S1P include growth related effects, such as proliferation, differentiation, cell survival and apoptosis, and cytoskeletal effects, such as chemotaxis, aggregation, adhesion, morphological change and secretion. The molecule has been implicated in control of angiogenesis, inflammation, heart-rate and tumour progression, and may play an important role in a number of disease states, such as atherosclerosis, and breast and ovarian cancer []. Recently, 5 G protein-coupled receptors have been identified that act as high affinity receptors for S1P, and also as low affinity receptors for the related lysophospholipid, SPC []. EDG-1, EDG-3, EDG-5 and EDG-8 share a high degree of similarity, and are also referred to as lpB1, lpB3, lpB2 and lpB4, respectively. EDG-6 is referred to as lpC1, reflecting its more distant relationship to the other S1P receptors.EDG-6 is expressed predominantly in lymphoid and haematopoietic tissues andin lung, a distribution that is quite restricted relative to other EDGfamily members []. Binding of S1P to the receptor leads to activation of phospholipase C and MAP kinases in a pertussis toxin sensitive manner, through coupling to proteins of the Gi class. Whether EDG-6 can couple to any other G protein families is currently not known [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Pheromones have evolved in all animal phyla, to signal sex and dominancestatus, and are responsible for stereotypical social and sexual behaviour among members of the same species. In mammals, these chemical signals are believed to be detected primarily by the vomeronasal organ (VNO), a chemosensory organ located at the base of the nasal septum []. The VNO is present in most amphibia, reptiles and non-primate mammals but is absent in birds, adult catarrhine monkeys and apes []. An active role for the human VNO in the detection of pheromones is disputed; the VNO is clearly present in the foetus but appears to be atrophied or absent in adults. Three distinct families of putative pheromone receptors have been identified in the vomeronasal organ (V1Rs, V2Rs and V3Rs). All are G protein-coupled receptors but are only distantly related to the receptors of the main olfactory system, highlighting their different role [].The V1 receptors share between 50 and 90% sequence identity but have littlesimilarity to other families of G protein-coupled receptors. They appear tobe distantly related to the mammalian T2R bitter taste receptors and therhodopsin-like GPCRs []. In rat, the family comprises 30-40 genes. These are expressed in the apical regions of the VNO, in neurons expressing Gi2. Coupling of the receptors to this protein mediates inositol trisphosphate signalling []. A number of human V1 receptor homologues have also been found. The majority of these human sequences are pseudogenes []but an apparently functional receptor has been identified that is expressed in the human olfactory system [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length []. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors [, , , ]. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.Pheromones have evolved in all animal phyla, to signal sex and dominancestatus, and are responsible for stereotypical social and sexual behaviour among members of the same species. In mammals, these chemical signals are believed to be detected primarily by the vomeronasal organ (VNO), a chemosensory organ located at the base of the nasal septum []. The VNO is present in most amphibia, reptiles and non-primate mammals but is absent in birds, adult catarrhine monkeys and apes []. An active role for the human VNO in the detection of pheromones is disputed; the VNO is clearly present in the foetus but appears to be atrophied or absent in adults. Three distinct families of putative pheromone receptors have been identified in the vomeronasal organ (V1Rs, V2Rs and V3Rs). All are G protein-coupled receptors but are only distantly related to the receptors of the main olfactory system, highlighting their different role [].The V2 receptors are members of GPCR family 3 and have close similarity to the extracellular calcium-sensing receptors []. Rodents appear to have around 100 functional V2 receptors and many pseudogenes []. These receptors are expressed in the basal regions of VNO, where they couple to G proteins to mediate inositol trisphosphate responses []. Homologues have also been identified in fish [], and the ligand specificity of one such receptor has been determined: a receptor from goldfish olfactory epithelium has been reported to bind basic amino acids, which are odorants for fish [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified in teleost fish []. In fish, MCH is released from the pituitary and causes lightening of skin pigment cells through pigment aggregation [, ]. In mammals, MCH is predominantly expressed in the hypothalamus, and functions as a neurotransmitter in the control of a range of functions []. A major role of MCH is thought to be in the regulation of feeding: injection of MCH into rat brains stimulates feeding; expression of MCH is upregulated in the hypothalamus of obese and fasting mice; and mice lacking MCH are lean and eat less [, ]. MCH and alpha melanocyte-stimulating hormone (alpha-MSH) have antagonistic effects on a number of physiological functions. Alpha-MSH darkens pigmentation in fish and reduces feeding in mammals, whereas MCH increases feeding [, ].MCH receptor 1 (MCHR1, previously known as SLC1) is a class I GPCR [, ]. Expression of the receptor has been found at highest levels in the brain, with moderate levels in the eye and skeletal muscle, and lower levels in the tongue and pituitary. In the brain, the receptor is expressed extensively in the hippocampus, olfactory regions and medial nucleus accumbens, a distribution that corresponds to connections between MCH-containing neurons and areas of the brain involved in taste and olfaction []. The receptor is also found in parts of the hypothalamus, such as the ventromedial nucleus, that are known to regulate feeding and metabolism. The MCH receptor is expressed at moderate levels in the substantia nigra, ventral tegmental area and amygdala, suggesting that MCH may modulate the dopaminergic system. Expression has also been found in the locus coeruleus, indicating a possible role in the control of noradrenaline responses, including vigilance, attention, memory and sleep. Binding of MCH to the receptor results in inhibition of forskolin-stimulated cyclic AMP accumulation in a pertussis toxin sensitive manner, release of intracellular calcium in a partially pertussis toxin sensitive manner and activation of MAP kinase in a partially protein kinase C dependent manner []. This indicates that the MCH receptor is capable of coupling to G proteins of the Gi, Go and Gq classes.
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [, , , ]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [, ]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity. All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin. CAPs bind G-actin. In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase []. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin []. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.This entry represents CAP proteins from various organisms.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) andbeta-endorphin are peptide products of pituitary pro-opiomelanocortin.ACTH regulates synthesis and release of glucocorticoids and aldosteronein the adrenal cortex; it also has a trophic action on these cells.ACTH and beta-endorphin are synthesised and released in response tocorticotrophin-releasing factor at times of stress (heat, cold, infections,etc.) - their release leads to increased metabolism and analgesia.MSH has a trophic action on melanocytes, and regulates pigment productionin fish and amphibia. The ACTH receptor is found in high levels inthe adrenal cortex - binding sites are present in lower levels in theCNS. The MSH receptor is expressed in high levels in melanocytes,melanomas and their derived cell lines. Receptors are found in lowlevels in the CNS. MSH regulates temperature control in the septal regionof the brain and releases prolactin from the pituitary.A further gene, which encodes a melanocortin receptor that is functionallydistinct from the ACTH and MSH receptors, has also been characterised [, , ].The protein contains ~323 amino acids, with calculated molecular mass of35,800 Da, and potential N-linked glycosylation and phosphorylation sites[]. The melanocortin 3 receptor (MC3-R) is found in neurons of the arcuatenucleus known to express proopiomelanocortin and in a subset of the nucleito which these neurons send projections []. The MC3-R is 43% identical tothe MSH receptor present in melanocytes and is strongly coupled to adenylylcyclase [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) andbeta-endorphin are peptide products of pituitary pro-opiomelanocortin.ACTH regulates synthesis and release of glucocorticoids and aldosteronein the adrenal cortex; it also has a trophic action on these cells.ACTH and beta-endorphin are synthesised and released in response tocorticotrophin-releasing factor at times of stress (heat, cold, infections,etc.) - their release leads to increased metabolism and analgesia.MSH has a trophic action on melanocytes, and regulates pigment productionin fish and amphibia. The ACTH receptor is found in high levels inthe adrenal cortex - binding sites are present in lower levels in theCNS. The MSH receptor is expressed in high levels in melanocytes,melanomas and their derived cell lines. Receptors are found in lowlevels in the CNS. MSH regulates temperature control in the septal regionof the brain and releases prolactin from the pituitary.This entry represents Melanocortin receptor 3-5 (MC3-5R) from chordates. These protein are receptors for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. MC3R is required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain []. MC4R plays a central role in energy homeostasis and somatic growth [, , ]. MC5R is a possible mediator of the immunomodulation properties of melanocortins, playing a role in immune reaction and inflammatory response as well as in the regulation of sexual behaviour, thermoregulation, and exocrine secretion [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Parathyroid hormone (PTH) is involved in calcium homeostasis within the body in combination with calcitonin and vitamin D. PTH is released in response to hypocalcaemia and stimulates a rise in blood calcium; the converse is true for calcitonin. The principle targets for PTH are bone and kidney. Antagonists at the PTH receptor are of potential clinical use in the treatment of hyperparathyroidism and short-term hypercalcaemic states. In addition to its presence in bone and kidney, the receptor is found in lower levels in blood vessels, where it mediates vasodilation. The principle second messenger pathway is activation of adenylyl cyclase through G proteins. In addition, PTH stimulates phosphoinositide metabolism on the expressed receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C and phospholipase D, as well as cytosolic protein kinase activation. The play an important role in the regulation of the cardiovascular system [, , ]and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels [, ]. As a result, endothelins are implicated in a number of vascular diseases, including the heart, general circulation and brain [, , ]. Endothelins stimulate the contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferens, stomach) and stimulate secretion in several tissues e.g., kidney, liver and adrenals [, , ]. Endothelins have also been implicated in a variety of pathophysiological conditions associated with stress including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure [].Two endothelin receptor subtypes have been isolated and identified, endothelin A receptor(ETA) and endothelin B receptor (ETB) [, , , ], and are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family (GPCRA) which stimulate multiple effectors via several types of G protein []. ETA and ETB receptors are both widely distributed, ETA receptors are mainly located on vascular smooth muscle cells, whereas ETB receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells [, ]. ETA receptors are considered to be the primary vasoconstrictor and growth-promoting receptor, and the binding of endothelin to ETA increases vasoconstriction (contraction of the blood vessel walls) and the retention of sodium, leading to increased blood pressure []. Endothelin B receptor on the other hand not only inhibits cell growth and vasoconstriction in the vascular system but also functions as a "clearance receptor". This receptor-mediated clearance mechanism is particularly important in the lung, which clears about 80% of circulating endothelin-1 [, ].Both receptors are localised to non-vascular structures such as epithelial cells as well as occurring in the central nervous system (CNS) on glial cells and neurones, where they are thought to mediate neurotransmission and vascular functions [].This entry represents the endothelin A receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents VIPR-2.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionaryrelationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAPtype I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents the PACAP-1 receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length []. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors [, , , ]. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.The metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca2+intracellular signalling pathway [, , , ]. At least eight sub-types of metabotropic receptor (GRM1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.mRNA for GRM1 is widespread in the brain and is abundant in neuronal cells in hippocampaldentate gyrus and CA2-3 regions, cerebellum Purkinje cells, olfactory bulband thalamic nuclei. GRM1 activates the phophoinositide pathway. It is thought to participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum [, ]. Like GRM5 [], it is a potential therapeutic target for several diseases []. Crystallisation of its seven transmembrane domain shows a similar structure to this seen in the entire GPCR protein family [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.EP3 receptors mediate contraction in a wide range of smooth muscles,including gastrointestinal and uterine. They also inhibit neurotransmitter release in central and autonomic nerves through a presynaptic action,and inhibit secretion in glandular tissues (e.g., acid secretion fromgastric mucosa, and sodium and water reabsorption in the kidney). mRNAis found in high levels in the kidney and uterus, and in lower levels inthe brain, thymus, lung, heart, stomach and spleen. The receptors activateadenylate cyclase via an uncharacterised G-protein, probably of the Gi/Goclass.Sequence analysis shows the EP3 receptors to fall into distinct classes,based on their N- and C-terminal and loop signatures. For convenience, wehave designated these classes types 1 to 3.
Potassium channels are the most diverse group of the ion channel family [, ]. They are important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers []. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes []. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+channels; and three types of calcium (Ca)-activated K+channels (BK, IK and SK) []. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K+channel alpha-subunits that possess two P-domains. These are usually highly regulated K+selective leak channels.Two types of beta subunit (KCNE and KCNAB) are presently known to associate with voltage-gated alpha subunits (Kv, KCNQ and eag-like). However, not all combinations of alpha and beta subunits are possible. The KCNE family of K+ channel subunits are membrane glycoproteins that possess a single transmembrane (TM) domain. They share no structural relationship with the alpha subunit proteins, which possess pore forming domains. The subunits appear to have a regulatory function, modulating the kinetics and voltage dependence of the alpha subunits of voltage-dependent K+ channels. KCNE subunits are formed from short polypeptides of ~130 amino acids, and are divided into five subfamilies: KCNE1 (MinK/IsK), KCNE2 (MiRP1), KCNE3 (MiRP2), KCNE4 (MiRP3) and KCNE1L (AMMECR2). KCNE3 is known to associate with the pore forming subunits KCNQ1, KCNQ4,HERG and Kv3.4. KCNE3 forms complexes with Kv3.4 in skeletal muscle -KCNE3 mutations have been identified in families with skeletal muscledisorders []. In the intestine, KCNE3 associates with KCNQ1 to formchannels that are stimulated by cAMP and are thought to be involved insecretory diarrhoea and cystic fibrosis [].
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not been demonstrated.This entry represents the neuropeptide Y1 receptor, which is present in smooth muscle such as the intestine and blood vessels [, , ]. The Y1 receptor are believed to have a predominantly postsynaptic location, and are involved in the inhibition of adenylyl cyclase through a pertussis-toxin-sensitive G-protein, probably of the Gi protein class []. There is also evidence that Y1 can stimulate an increase in intracellular calcium independently of the phosphoinositide pathway [].
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not beendemonstrated.This entry represents the neuropeptide Y5 receptor, which has less than 35% overall identity to known Y-type receptors []. It is found primarily in the central nervous system [], including the paraventricular nucleus of the hypothalamus []. The Y5 receptor has been postulated to be the 'feeding' receptor, and may provide new approaches for the study and treatment of obesity and eating disorders [, , , ].
Members of this group are signal transduction proteins that are direct oxygen sensors and are involved in regulation of cellular processes via the effector molecule cyclic diguanylate (c-di-GMP, bis(3',5')-cyclic diguanylic acid). They contain PAS/PAC, GGDEF, and EAL domains and have diguanylate cyclase and phosphodiesterase activities. Related groups with similar domain architectures contain different versions of PAS/PAC domain, and are thought to have different, often not yet determined biological functions.Escherichia coli Dos (YddU or DosP) and Komagataeibacter xylinus (Gluconacetobacter xylinus or Acetobacter xylinum) PdeA1 proteins have been shown to be direct, haem-based oxygen sensors [, , ]. Their N-terminal PAS domains are responsible for haem-binding [, ]. PAS/PAC is a ubiquitous intracellular sensory domain. It is located in the cytoplasm and sense changes in redox potential in the electron transport system or overall cellular redox status. PAS domains can monitor changes in light, oxygen or small ligands in a cell, and sense environmental factors that cross the cell membrane and/or affect cell metabolism [, , ]. In the haem-containing subgroup of PAS domains, the haem pocket acts as a ligand-specific trap []. The ligand binding to a haem-containing PAS domain leads to either activation or inhibition of a regulated (catalytic) domain (here, GGDEF and/or EAL domains). Phosphodiesterase activity with cAMP of E. coli Dos has been shown to be regulated by the haem redox state []. Similarly, Komagataeibacter xylinus PdeA1 is regulated by reversible binding of O2to the haem [].The catalytic function of the members of this group has also been experimentally determined.Cyclic di-GMP (c-di-GMP) is the specific nucleotide regulator of beta-1,4-glucan (cellulose) synthase in Komagataeibacter xylinus []. In a study of the regulation of biosynthesis of extracellular cellulose in Komagataeibacter xylinus [], the search for the enzymes that synthesise and hydrolyse cyclic di-GMP resulted in the identification of six proteins with identical domain architecture containing PAS, GGDEF and EAL domains. Three of them exhibited diguanylate cyclase activity (Dgc1-3), and three others - phosphodiesterase activity (PdeA1-3) [, ]. Likewise, E. coli Dos has been shown to have phosphodiesterase activity [].Genetic complementation using genes from three different bacteria encoding proteins with GGDEF domains as the only element in common indicate that the GGDEF domain is responsible for the diguanylate cyclase activity of these proteins []. Even prior to these results, the notion that the GGDEF domain is a diguanylate cyclase was supported by the detailed analysis of its sequence, which shows conservation of the proposed nucleotide-binding loop in alignment with eukaryotic adenylate cyclases []. By exclusion, the EAL domain emerged as the best candidate for the role of c-di-GMP phosphodiesterase. Indeed, the sequence of this domain contains several conserved aspartates, which could participate in metal binding and form a phosphodiesterase active site []. It is not clear what differences make one subgroup of these proteins to act as phosphodiesterases, and another - as diguanylate cyclases, while containing both domains.For additional information please see [, ].
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [, , , ]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [, ]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity. All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin. CAPs bind G-actin. In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase []. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin []. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.This entry represents the C-terminal domain of CAP proteins, which is responsible for G-actin-binding. This domain has a superhelical structure, where the superhelix turns are made of two β-strands each [].
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [, , , ]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [, ]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity. All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin. CAPs bind G-actin. In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase []. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin []. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.This entry represents the N-terminal domain of CAP proteins. This domain has an all-alpha structure consisting of six helices in a bundle with a left-handed twist and an up-and-down topology [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.EP3 receptors mediate contraction in a wide range of smooth muscles,including gastrointestinal and uterine. They also inhibit neurotransmitter release in central and autonomic nerves through a presynaptic action,and inhibit secretion in glandular tissues (e.g., acid secretion fromgastric mucosa, and sodium and water reabsorption in the kidney). mRNAis found in high levels in the kidney and uterus, and in lower levels inthe brain, thymus, lung, heart, stomach and spleen. The receptors activateadenylate cyclase via an uncharacterised G-protein, probably of the Gi/Goclass.Sequence analysis shows the EP3 receptors to fall into distinct classes,based on their N- and C-terminal and loop signatures. For convenience, wehave designated these classes types 1 to 3.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Hypothalamic peptide hormones regulate secretion of anterior pituitary hormones, such as growth hormone, follicle stimulating hormone, luteinisinghormone and thyrotropin. A novel bioactive peptide has been identified from bovine hypothalamus and found to increase prolactin secretion from the anterior pituitary []. This peptide - prolactin-releasing peptide (PrRP) - is a member of the structurally related RF-amide family, which includes neuropeptide FF []. The peptide exists in two forms: a 31-amino acid form and a truncated 20-amino acid form []. PrRP has been found in the medulla oblongata, hypothalamus and pituitary, as well as in a number of other tissues. This distribution suggests the peptide may have other roles in addition to prolactin release [].The receptor for PrRP was identified to be an orphan receptor, previously known as GPR10 []. This receptor is expressed in the central nervous system with highest levels in the pituitary. Expression has also been detected in the cerebellum, brainstem, hypothalamus, thalamus and spinal cord in rat []. Binding of PrRP to the receptor results in activation of extracellular signal-related kinase (ERK) in a mainly pertussis toxin sensitive manner, suggesting coupling to Gi/o proteins []. PrRP can also cause increases in intracellular calcium and activation of c-Jun N-terminal protein kinase (JNK) in a pertussis toxin insensitive manner, indicating that the receptor can also couple to Gq proteins, depending on the cell type in which it is expressed [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets,and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C and phospholipase D, as well as cytosolic protein kinase activation. The play an important role in the regulation of the cardiovascular system [, , ]and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels [, ]. As a result, endothelins are implicated in a number of vascular diseases, including the heart, general circulation and brain [, , ]. Endothelins stimulate the contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferens, stomach) and stimulate secretion in several tissues e.g., kidney, liver and adrenals [, , ]. Endothelins have also been implicated in a variety of pathophysiological conditions associated with stress including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure [].Two endothelin receptor subtypes have been isolated and identified, endothelin A receptor(ETA) and endothelin B receptor (ETB) [, , , ], and are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family (GPCRA) which stimulate multiple effectors via several types of G protein []. ETA and ETB receptors are both widely distributed, ETA receptors are mainly located on vascular smooth muscle cells, whereas ETB receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells [, ]. ETA receptors are considered to be the primary vasoconstrictor and growth-promoting receptor, and the binding of endothelin to ETA increases vasoconstriction (contraction of the blood vessel walls) and the retention of sodium, leading to increased blood pressure []. Endothelin B receptor on the other hand not only inhibits cell growth and vasoconstriction in the vascular system but also functions as a "clearance receptor". This receptor-mediated clearance mechanismis particularly important in the lung, which clears about 80% of circulating endothelin-1 [, ].Both receptors are localised to non-vascular structures such as epithelial cells as well as occurring in the central nervous system (CNS) on glial cells and neurones, where they are thought to mediate neurotransmission and vascular functions [].This entry represents the endothelin B receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].In addition to their role in energy metabolism, purines (especiallyadenosine and adenine nucleotides) produce a wide range of pharmacologicaleffects mediated by activation of cell surface receptors. Distinctreceptors exist for adenosine. In the periphery, the main effects ofadenosine include vasodilation, bronchoconstriction, immunosuppresion,inhibition of platelet aggregation, cardiac depression, stimulation ofnociceptive afferents, inhibition of neurotransmitter release andinhibition of the release of other factors, e.g. hormones. In the CNS,adenosine exerts a pre- and post-synaptic depressant action, reducing motoractivity, depressing respiration, inducing sleep and relieving anxiety. Thephysiological role of adenosine is thought to be to adjust energy demandsin line with oxygen supply. Many of the clinical actions of methylxanthinesare thought to be mediated through antagonism of adenosine receptors. Foursubtypes of receptor have been identified, designated A1, A2A, A2B and A3.A3 receptors are found in high levels in the testis, and in lower levels inthe lung, kidney and heart. They are also found in low levels in regionsof the CNS (including the cerebral cortex, striatum and olfactory bulb). Thepresence in high levels in the testis has led to the suggestion that it mayplay a role in reproduction. The A3 receptor inhibits adenylyl cyclasethrough a pertussis-toxin-sensitive G-protein, probably belonging to theGi/Go class.
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not been demonstrated.This entry represents the neuropeptide Y6 receptor, which shares 60% sequence identity with the Y1 receptor. Its pharmacology resembles that of the Y1 receptor and is distinct from that described for Y2, Y3 and Y4 receptors []. In mice, the Y6 receptor is expressed within discrete regions of the hypothalamus, including the suprachiasmatic nucleus, anterior hypothalamus, bed nucleus stria terminalis, and the ventromedial nucleus, with no localisation apparent elsewhere in the brain; and in the testis. The absence of this protein leads to major reduction in bone mass without modifying bone length [, , ].
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not been demonstrated.This entry represents the neuropeptide Y2 receptor. It is found in high levels in rat hippocampus [], superficial layers of the cortex, certain thalamic nuclei, lateral septum, and anterior olfactory nuclei [, , ], lower levels are found in striatum. The receptors are also found in high levels in smooth muscle, such as vas deferens and intestine [], kidney proximal tubules and in cell lines. Y2 receptors are believed to have a predominantly presynaptic location, and are involved in inhibition of adenylyl cyclase and voltage dependent calcium channels via a pertussis-toxin-sensitive G-protein, probably of the Gi protein class [, ].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) andbeta-endorphin are peptide products of pituitary pro-opiomelanocortin.ACTH regulates synthesis and release of glucocorticoids and aldosteronein the adrenal cortex; it also has a trophic action on these cells.ACTH and beta-endorphin are synthesised and released in response tocorticotrophin-releasing factor at times of stress (heat, cold, infections,etc.) - their release leads to increased metabolism and analgesia.MSH has a trophic action on melanocytes, and regulates pigment productionin fish and amphibia. The ACTH receptor is found in high levels inthe adrenal cortex - binding sites are present in lower levels in theCNS. The MSH receptor is expressed in high levels in melanocytes,melanomas and their derived cell lines. Receptors are found in lowlevels in the CNS. MSH regulates temperature control in the septal regionof the brain and releases prolactin from the pituitary.A further gene, which encodes a melanocortin receptor that is functionallydistinct from the ACTH and MSH receptors, has also been characterised [, , , , ].The protein contains ~300 amino acids, with calculated molecular mass of~36kDa, and potential N-linked glycosylation and phosphorylation sites[]. The melanocortin 5 receptor (MC5-R) mediates increase in cAMPaccumulation with a characteristic pharmacology []. Very low expressionlevels have been detected in brain, while high levels are found in adrenals,stomach, lung and spleen []. In situ hybridisation studies have also shownthe MC5 receptor to be expressed in the three layers of the adrenal cortex,predominantly in the aldosterone-producing zona glomerulosa cells [].Structure-activity studies have indicated that N- and C-terminal portionsof alpha-MSH appear to be key determinants in the activation of mouseMC5R, while the melanocortin core heptapeptide sequence is devoid ofpharmacological activity [].
Human epidermal growth factor (EGF)-like module containing mucin-like hormone receptor 1 (EMR1) is a surface receptor of unknown function that belongs to the EGF-seven-transmembrane (EGF-TM7) family of G-protein coupled receptors []. Human EMR1 has been reported to be expressed exclusively on eosinophils []. It is the the human homologue of F4/80, a monoclonal antibody that recognises a Mus musculus (Mouse) macrophage-restricted cell surface glycoprotein that has been extensively used to characterise macrophage populations in a wide range of immunological studies []. Little is known about its possible role in macrophage differentiation and function. The sequence of the F4/80 protein is similar to two protein superfamilies: the N-terminal region contains seven epidermal growth factor (EGF)-like domains, while the C-terminal region contains seven hydrophobic regions whose signature is consistent with membership of the secretin-like superfamily of GPCRs. The EGF and GPCR domains are separated from each other by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties [].This family also comprises EMR3, a marker for mature granulocytes [], and EMR4 [, ].G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Corticotropin-releasing factor (CRF) is the principal neuroregulator of the hypothalamic-pituitary-adrenocortical axis, playing an important role in coordinating the endocrine, autonomic and behavioral responses to stress and immune challenge []. The CRF receptor has been found in human cortex tissue, pituitary, brainstem and testis []. The protein comprises 415 amino acid residues with the characteristic 7TM architecture of the secretin-like GPCR superfamily. Three isoforms (designated CRF-R1, CRF-R2 and CRF-R3) are produced as a result of alternative splicing of the same gene: CRF-R1 appears to be the predominant form; CRF-R3 does not bind to CRF with a high affinity []. CRF and the related urocortin peptides (Ucn 1-3, also known as UCN, UCN2 and UCN3) mediate their actions through two CRF1 and CRF2 [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. The Adhesion G Protein-Coupled Receptors (aGPCRs) constitute an evolutionary ancient membrane protein family. The receptors contain a 7-TM domain with phylogeny suggesting ancestry to the Family B/2 (secretin receptor family, Class B/2) G-Protein-Coupled Receptors. aGPCRs are distinguished by their large amino-terminal regions that typically contain multiple modular motifs such as EGF (Epidermal Growth Factor-like), cadherin and immunoglobulin domains as well as novel lineage-specific structures. A defining feature of aGPCRs is the GPCR Autoproteoolysis-Inducing (GAIN) domain linking the N-terminal structure to the 7-TM region. Most aGPCRs undergo autocatalytic cleavage here, at the GPCR proteolysis site (GPS) into N-terminal and C-terminal fragments [].Adhesion G protein-coupled receptor E2 (ADGRE2) protein is a member of the EGF-7TM subclass of aGPCRs and has an N-terminal extracellular region that consists of 5 tandem EGF-like adhesion domains, an internal mucin-like stalk domain containing a short G-protein proteolytic site and a C-terminal seven-pass transmembrane domain. ADGRE2 undergoes autocatalytic cleavage within its G-protein proteolytic site motif. It is expressed predominantly in myeloid leukocytes but also on the surface of lung mast cells and the HMC1 human mast-cell line. The endogenous ligand is dermatan sulfate. The most closely related paralogue of ADGRE2 is ADGRE5 (also called CD97). Ligand binding of ADGRE5 mediates cell-cell adhesion of leukocytes and mediates an essential role in leukocyte migration [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. The major physiological role of calcitonin is to inhibit bone resorptionthereby leading to a reduction in plasma Ca2+. Further, it enhances excretion of ions in the kidney, prevents absorption of ions in the intestine, and inhibits secretion in endocrine cells (e.g. pancreas andpituitary). In the CNS, calcitonin has been reported to be analgesicand to suppress feeding and gastric acid secretion. It is used to treatPaget's disease of the bone. Calcitonin receptors are found predominantlyon osteoclasts or on immortal cell lines derived from these cells. It isfound in lower amounts in the brain (e.g. in hypothalamus and pituitarytissues) and in peripheral tissues (e.g. testes, kidney, liver andlymphocytes). It has also been described in lung and breast cancer celllines. The predominant signalling pathway is activation of adenylyl cyclasethrough G proteins, but calcitonin has also been described to have both stimulatoryand inhibitory actions on the phosphoinositide pathway. Calcitonin gene-related peptide (CGRP) is a neuropeptide with diversebiological effects including potent vasodilator activity []. Messenger RNA for this receptor is predominantly expressed in the lung and heart, with specific localisation to lung alveolar cells and cardiac myocytes []. In the rat lung, it is associated with blood vessels; the gene may therefore play an important role in the maintenance of vascular tone []. mRNA is also found in the cerebellum []. The ligand for this receptor-like protein remains to be discovered.
Latrophilins are a family of secretin-like GPCRs that can be subdividedinto 3 subtypes: LPH1, LPH2 and LPH3. LPH1 is a brain-specific calciumindependent receptor of alpha-latrotoxin (LTX), a neurotoxin. It is the affinity of this form of the receptor for LTX that gives the family its name. LPH2 and LPH3, whilst sharing extensive sequence similarity to LPH1, do not bind LTX. LPH2 is distributed throughout most tissues, whereas LPH3 is also brain-specific []. The endogenous ligand(s) for these receptors are at present unknown. Binding of LTX to LPH1 stimulates exocytosis and the subsequent release of large amounts of neurotransmitters from neuronal and endocrine cells. The latrophilins possess up to 7 sites of alternative splicing; the resulting number of possible splice variants leads to a highly variable family of proteins.Structurally, these proteins have a seven-transmembrane region and a large extracellular N-terminal region which consists of several domains: a rhamnose binding lectin (RBL) domain, an olfactomedin-like (OLF) domain followed by a Serine/Threonine rich domain that is O-linked glycosylated, a hormone binding (HR) domain; and a GPCR Autoproteolysis INducing (GAIN) domain [].G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Three human secretin-like GPCRs that are expressed specifically in thebrain, and appear to have a role in the inhibition of angiogenesis, havebeen identified and named BAI (brain-specific angiogenesis inhibitor) 1-3[]. In addition to the characteristic 7 TM domains, the BAIs also have alarge extracellular domain containing a number of thrombospondin type 1 repeats - these have been shown to inhibit in vivo angiogenesis induced bybFGF in rat cornea. BAI1 has been found to be transcriptionally regulated by p53 and is absent in many glioblastoma cell lines, suggestingthat it may play an important role in suppression of the disease.BAI is also known as adhesion G protein-coupled receptor B (ADGRB). Disregulation of these GPCRs (aGPCRs) has been observed in cancer [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Neuromedin U is a neuropeptide, first isolated from porcine spinal cord andexpressed widely in the gastrointestinal, genitourinary and central nervoussystems []. Neuromedin U has potent contractile activity on smooth muscle and this activity is believed to reside within the C-terminal portion of the peptide, which is highly conserved between species. Other roles for the peptide include: regulation of blood flow and ion transport in the intestine, regulation of adrenocortical function and increased bloodpressure []. The roles of neuromedin U in the central nervous systemare poorly understood, but may include: regulation of food intake,neuroendocrine control, modulation of dopamine actions and involvement inneuropsychiatric disorders. Two G protein-coupled receptor subtypes,with differing expression patterns, have been identified and shown to bindneuromedin U.The neuromedin U type 1 receptor (NMU1) is expressed predominantly in theperiphery, with highest levels in the gastrointestinal and urogenitalsystems, particularly in the testes []. The receptor is also found in thekidney, pancreas, lung, trachea, adrenal cortex, liver and mammary glands[]. Within the small intestine and ileum, NMU1 is specifically expressed in goblet cells. In the central nervous system, the receptor isexpressed only at much lower levels and has been detected most abundantlyin the cerebellum, dorsal root ganglia, hippocampus and spinal cord.Binding of neuromedin U to the receptor results in phospholipase Cactivation and increased intracellular calcium concentrations throughcoupling to Gq proteins.
Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins []. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.The voltage-dependent calcium channel gamma (VDCCG) subunit family consistsof at least 8 members, which share a number of common structural features[]. Each member is predicted to possess 4 transmembrane domains, with intracellular N- and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved andcontain a consensus site for phosphorylation by cAMP and cGMP-dependentprotein kinases, and a target site for binding by PDZ domain proteins [].The VDCCG-2 subunit (also known as stargazin) was isolated by identifying the locus of the genetic disruption in the epileptic mouse mutant lineknown as stargazer []. VDCCG-2 subunits are brain specific and enriched in synaptic plasma membranes. In vitro studies using recombinant P/Q-type calcium channels show that VDCCG-2 subunit expression increases steady-statechannel inactivation, leading to the suggestion that, in stargazer mutants, inappropriate calcium entry may contribute to the seizure phenotype.VDCCG-2 subunits are also implicated in cellular trafficking. They interact with ionotropic glutamate AMPA receptor subunits, a process that has beenshown to be essential in delivering functional AMPA receptors to the surfacemembranes of cerebellar granule cells []. In addition, VDCCG-2 subunits are capable of associating with PDZ proteins, such as PSD-95, through their C-terminal PDZ binding domains. This interaction is required to target AMPAreceptors to cerebellar synapses.
Carbamoyl phosphate synthase (CPSase) is a heterodimeric enzyme composed of a small and a large subunit (with the exception of CPSase III, see below). CPSase catalyses the synthesis of carbamoyl phosphate from biocarbonate, ATP and glutamine () or ammonia (), and represents the first committed step in pyrimidine and arginine biosynthesis in prokaryotes and eukaryotes, and in the urea cycle in most terrestrial vertebrates [, ]. CPSase has three active sites, one in the small subunit and two in the large subunit. The small subunit contains the glutamine binding site and catalyses the hydrolysis of glutamine to glutamate and ammonia. The large subunit has two homologous carboxy phosphate domains, both of which have ATP-binding sites; however, the N-terminal carboxy phosphate domain catalyses the phosphorylation of biocarbonate, while the C-terminal domain catalyses the phosphorylation of the carbamate intermediate []. The carboxy phosphate domain found duplicated in the large subunit of CPSase is also present as a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase () (ACC), propionyl-CoA carboxylase () (PCCase), pyruvate carboxylase () (PC) and urea carboxylase ().Most prokaryotes carry one form of CPSase that participates in both arginine and pyrimidine biosynthesis, however certain bacteria can have separate forms. The large subunit in bacterial CPSase has four structural domains: the carboxy phosphate domain 1, the oligomerisation domain, the carbamoyl phosphate domain 2 and the allosteric domain []. CPSase heterodimers from Escherichia coli contain two molecular tunnels: an ammonia tunnel and a carbamate tunnel. These inter-domain tunnels connect the three distinct active sites, and function as conduits for the transport of unstable reaction intermediates (ammonia and carbamate) between successive active sites []. The catalytic mechanism of CPSase involves the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain.Eukaryotes have two distinct forms of CPSase: a mitochondrial enzyme (CPSase I) that participates in both arginine biosynthesis and the urea cycle; and a cytosolic enzyme (CPSase II) involved in pyrimidine biosynthesis. CPSase II occurs as part of a multi-enzyme complex along with aspartate transcarbamoylase and dihydroorotase; this complex is referred to as the CAD protein []. The hepatic expression of CPSase is transcriptionally regulated by glucocorticoids and/or cAMP []. There is a third form of the enzyme, CPSase III, found in fish, which uses glutamine as a nitrogen source instead of ammonia []. CPSase III is closely related to CPSase I, and is composed of a single polypeptide that may have arisen from gene fusion of the glutaminase and synthetase domains []. This entry represents the ATP-binding domain found in the large subunit of carbamoyl phosphate synthase, as well as in other proteins, including acetyl-CoA carboxylases and pyruvate carboxylases.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Corticotropin-releasing factor (CRF) is the principal neuroregulator of the hypothalamic-pituitary-adrenocortical axis, playing an important role in coordinating the endocrine, autonomic and behavioral responses to stress and immune challenge []. The CRF receptor has been found in human cortex tissue, pituitary, brainstem and testis []. The protein comprises 415 amino acid residues with the characteristic 7TM architecture of the secretin-like GPCR superfamily. Three isoforms (designated CRF-R1, CRF-R2 and CRF-R3) are produced as a result of alternative splicing of the same gene: CRF-R1 appears to be the predominant form; CRF-R3 does not bind to CRF with a high affinity []. CRF and the related urocortin peptides (Ucn 1-3, also known as UCN, UCN2 and UCN3) mediate their actions through two CRF1 and CRF2 [].The sequence of the CRF-R is highly conserved from avian to mammalian species, the majority of the sequence divergence occuring in the putativesignal peptide and extracellular N-terminal domain []. Five additional amino acids are inserted in the N terminus of the avian receptor, and despite its overall similarity to the type 1 mammalian CRF-R, its ligand binding properties are similar to those of the type 2 receptor (i.e., has a higher affinity for urotensin I than for CRF) []. This entry includes CRF1 receptor (CRF1R, also known as CRHR1), which is activated by CRF and Ucn1, is expressed in brain areas including the pituitary, hypothalamus, amygdala and cortex. It is an interesting target to develop drug treatments for stress-related conditions such as anxiety, depression and irritable bowel syndrome [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. The major physiological role of calcitonin is to inhibit bone resorptionthereby leading to a reduction in plasma Ca2+. Further, it enhancesexcretion of ions in the kidney, prevents absorption of ions in theintestine, and inhibits secretion in endocrine cells (e.g. pancreas andpituitary). In the CNS, calcitonin has been reported to be analgesicand to suppress feeding and gastric acid secretion. It is used to treatPaget's disease of the bone. Calcitonin receptors are found predominantlyon osteoclasts or on immortal cell lines derived from these cells. It isfound in lower amounts in the brain (e.g. in hypothalamus and pituitarytissues) and in peripheral tissues (e.g. testes, kidney, liver andlymphocytes). It has also been described in lung and breast cancer celllines. The predominant signalling pathway is activation of adenylyl cyclasethrough guanine nucleotide-binding proteins (G proteins), but calcitonin has also been described to have both stimulatoryand inhibitory actions on the phosphoinositide pathway.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Growth hormone (GH)-releasing hormone (GHRH) belongs to the family of gut-neuropeptide hormones that includes glucagon, secretin and vasoactive intestinal peptide (VIP) []. The receptors for this peptide family involve similar signal transduction pathways - on hormone binding, they interact with G protein and cause stimulation of adenylate cyclase []. Acting through the GHRH receptor (GHRHR), GH plays a pivotal role in the regulation of GH synthesis and secretion in the pituitary, possibly serving other roles in different tissues []. Cryo-electron microscopy shows a hormone recognition pattern where an α-helical GHRH forms interactions involving all the extracellular loops, most TM helices, and a linker from GHRHR []. The human pituitary GHRHR is a 423-amino acid protein that has the characteristic 7TM signature of the secretin-like GPCR superfamily, sharing 47%, 42%, 35%, and 28% identity with receptors for VIP, secretin, calcitonin and PTH, respectively [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Glucagon-like peptide-1 (GLP-1), which is encoded by the glucagon gene and released from the gut in response to nutrients, is a potent stimulator of glucose-induced insulin secretion and proinsulin gene expression of pancreatic beta-cells [, ]. In humans, GLP-I exerts its physiological effect as an incretin. Patients with insulinoma tumors show uncontrolled insulin hypersecretion []. The GLP-I receptor binds GLP-1 with high affinity and couples to activation of adenylate cyclase []. The receptor specifically binds GLP-1 and not peptides of related structure and function, such as glucagon, gastric inhibitory peptide, VIP or secretin []. It is thought that GLP-I might have effects beyond the pancreas, including the cardiovascular and central nervous systems, where a receptor with the same ligand-binding specificity is found [].
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [, , , ]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [, ]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity. All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin. CAPs bind G-actin. In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase []. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin []. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.This entry represents the C-terminal domain of CAP proteins, which is responsible for G-actin-binding. This domain has a superhelical structure, where the superhelix turns are made of two β-strands each [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Latrophilins are a family of secretin-like GPCRs that can be subdividedinto 3 subtypes: LPH1, LPH2 and LPH3. LPH1 is a brain-specific calciumindependent receptor of alpha-latrotoxin (LTX), a neurotoxin. It is the affinity of this form of the receptor for LTX that gives the family its name. LPH2 and LPH3, whilst sharing extensive sequence similarity to LPH1, do not bind LTX. LPH2 is distributed throughout most tissues, whereas LPH3 is also brain-specific []. The endogenous ligand(s) for these receptors are at present unknown. Binding of LTX to LPH1 stimulates exocytosis and the subsequent release of large amounts of neurotransmitters from neuronal and endocrine cells. The latrophilins possess up to 7 sites of alternative splicing; the resulting number of possible splice variants leads to a highly variable family of proteins.Structurally, these proteins have a seven-transmembrane region and a large extracellular N-terminal region which consists of several domains: a rhamnose binding lectin (RBL) domain, an olfactomedin-like (OLF) domain followed by a Serine/Threonine rich domain that is O-linked glycosylated, a hormone binding (HR) domain; and a GPCR Autoproteolysis INducing (GAIN) domain [].This entry represents the C-terminal region of latrophilin.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].In addition to their role in energy metabolism, purines (especiallyadenosine and adenine nucleotides) produce a wide range of pharmacologicaleffects mediated by activation of cell surface receptors. Distinctreceptors exist for adenosine. In the periphery, the main effects ofadenosine include vasodilation, bronchoconstriction, immunosuppresion,inhibition of platelet aggregation, cardiac depression, stimulation ofnociceptive afferents, inhibition of neurotransmitter release andinhibition of the release of other factors, e.g. hormones. In the CNS,adenosine exerts a pre- and post-synaptic depressant action, reducing motoractivity, depressing respiration, inducing sleep and relieving anxiety. Thephysiological role of adenosine is thought to be to adjust energy demandsin line with oxygen supply. Many of the clinical actions of methylxanthinesare thought to be mediated through antagonism of adenosine receptors. Foursubtypes of receptor have been identified, designated A1, A2A, A2B and A3.A1 receptors are distributed widely in peripheral tissues (e.g., heart,adipose tissue, kidney, stomach and pancreas), where they have a mainlyinhibitory role, and are also found in peripheral nerves (e.g., in theintestine and vas deferens). In the CNS, they are present in highlevels, notably in the cerebral cortex, hippocampus, cerebellum, thalamusand striatum. The receptors inhibit adenylyl cyclase and voltage-dependentcalcium channels, and activate potassium channels through a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].GPCR Fungal pheromone mating factor receptors form a distinct family of G-protein-coupled receptors, and are also known as Class D GPCRs.The Fungal pheromone mating factor receptors STE2 and STE3 are integral membrane proteins that may be involved in the response to mating factors on the cell membrane [, , ]. The amino acid sequences of both receptors contain high proportions of hydrophobic residues grouped into 7 domains,in a manner reminiscent of the rhodopsins and other receptors believed tointeract with G-proteins. However, while a similar 3D framework has been proposed to account for this, there is no significant sequence similarity either between STE2 and STE3, or between these and the rhodopsin-type family: the receptors thereofore bear their own unique '7TM' signatures which is why they have been given their own GPCR group: Class D Fungal mating pheromone receptors.The STE3 gene in Saccharomyces cerevisiae is the cell-surface receptor that binds the13-residue lipopeptide a-factor. Several related fungal pheromone receptorsequences are known: these include pheromone B alpha 1 and B alpha 3, andpheromone B beta 1 receptors from Schizophyllum commune; pheromone receptor1 from Ustilago hordei; and pheromone receptors 1 and 2 from Ustilago maydis.Members of the family share about 20% sequence identity.U. maydis, a tetrapolar fungal species, has two genetically unlinkedloci that encode the distinct mating functions of cell fusion (the a locus)and subsequent sexual development and pathogenicity (the b locus) [].The a locus exists in two alleles, the mating type in each of which isdetermined by a set of two genes; one encodes a precursor for a lipopeptidemating factor, while the other specifies the receptor for the pheromonesecreted by cells of opposite mating type []. U. maydis thus employs anovel strategy to determine its mating type by providing the primarydeterminants of cell-cell recognition directly from the mating type locus[]. The bipolar species, U. hordei, contains both a and b loci;physical linkage of these loci in this bipolar fungus accounts for itsdistinct mating system [].This entry represents mating-type a receptors.
Potassium channels are the most diverse group of the ion channel family [, ]. Theyare important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers []. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes []. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+channels; and three types of calcium (Ca)-activated K+channels (BK, IK and SK) []. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K+channel alpha-subunits that possess two P-domains. These are usually highly regulated K+selective leak channels.KCNQ channels (also known as KQT-like channels) differ from other voltage-gated 6 TM helix channels, chiefly in that they possess no tetramerisation domain. Consequently, they rely on interaction with accessory subunits, or form heterotetramers with other members of the family []. Currently, 5 members of the KCNQ family are known. These have been found to be widely distributed within the body, having been shown to be expressed in the heart, brain, pancreas, lung, placenta and ear. They were initially cloned as a result of a search for proteins involved in cardiac arhythmia. Subsequently, mutations in other KCNQ family members have been shown to be responsible for some forms of hereditary deafness []and benign familial neonatal epilepsy [].The KCNQ2 channel subunit is thought to form active channels by hetero- tetramerisation with KCNQ3, although some K+ channel activity does results from the expression of KCNQ2 alone []. Channel function is modulated by phosphorylation, since experiments have demonstrated that an increase in intracellular cAMP concentration can enhance channel activity. Frameshift mutations in both KCNQ2 and KCNQ3 are associated with benign familial neonatal epilepsy [], a disorder where an infant begins to suffer convulsions, within the first three days of life. These symptoms usually disappear after approximately three months, but affected individuals have a higher than average chance of subsequently developing epilepsy (10-15%), in later life [].
Potassium channels are the most diverse group of the ion channel family [, ]. They are important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers []. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes []. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+channels; and three types of calcium (Ca)-activated K+channels (BK, IK and SK) []. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K+channel alpha-subunits that possess two P-domains. These are usually highly regulated K+selective leak channels.KCNQ channels (also known as KQT-like channels) differ from other voltage-gated 6 TM helix channels, chiefly in that they possess no tetramerisation domain. Consequently, they rely on interaction with accessory subunits, or form heterotetramers with other members of the family []. Currently, 5 members of the KCNQ family are known. These have been found to be widely distributed within the body, having been shown to be expressed in the heart, brain, pancreas, lung, placenta and ear. They were initially cloned as a result of a search for proteins involved in cardiac arhythmia. Subsequently, mutations in other KCNQ family members have been shown to be responsible for some forms of hereditary deafness []and benign familial neonatal epilepsy [].The KCNQ3 channel subunit is thought to form active channels by hetero- tetramerisation with KCNQ2, although some K+ channel activity does result from the expression of KCNQ3 alone []. Channel function is modulated by phosphorylation; experiments have demonstrated that an increase in intracellular cAMP concentration can enhance channel activity. Frameshift mutations in both KCNQ2 and KCNQ3 are associated with benign familial neonatal epilepsy [], a disorder in which infants suffer convulsions within the first 3 days of life. These symptoms usually disappear after about 3 months, but affected individuals have a higher than average chance of subsequently developing epilepsy (10-15%) in later life [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs(Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Neurotensin is a 13-residue peptide transmitter, sharing significantsimilarity in its 6 C-terminal amino acids with several other neuropeptides,including neuromedin N. This region is responsible for the biological activity, the N-terminal portion having a modulatory role. Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.The existence of 2 neurotensin receptor subtypes, with differing affinitiesfor neurotensin and differing sensitivities to the antihistamine levocabastine, was originally demonstrated by binding studies in rodent brain. Two neurotensin receptors (NT1 and NT2) with such properties have since been cloned and have been found to be G-protein-coupled receptor family members [].The NT2 receptor was cloned from rat, mouse and human brains based on itssimilarity to the NT1 receptor. The receptor was found to be a low affinity,levocabastine sensitive receptor for neurotensin. Unlike the high affinity,NT1 receptor, NT2 is insensitive to guanosine triphosphate and has low sensitivity to sodium ions []. Highest levels of expression of the receptor are found in the brain, in regions including: the olfactory system, cerebral and cerebellar cortices, hippocampus and hypothalamic nuclei. The distribution is distinct from that of the NT1 receptor, with only a fewareas (diagonal band of Broca, medial septal nucleus and suprachiasmatic nuclei) expressing both receptor subtypes. The receptor has also been found at lower levels in the kidney, uterus, heart and lung []. Activationof the NT2 receptor by non-peptide agonists suggests that the receptor cancouple to phospholipase C, phospholipase A2 and MAP kinase. A functionalresponse to neurotensin, however, is weak []or absent, and neurotensin appears to act as an antagonist of the receptor []. It has been suggested that a substance other than neurotensin may act as the natural ligand for this receptor.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Leukotrienes (LT) are potent lipid mediators derived from arachidonic acid metabolism. They can be divided into two classes, based on the presence or absence of a cysteinyl group. Leukotriene B4 (LTB4) does not contain such a group, whereas LTC4, LTD4, LTE4 and LTF4 are cysteinyl leukotrienes.LTB4 is one of the most effective chemoattractant mediators known, and is produced predominantly by neutrophils and macrophages. It is involved in a number of events, including: stimulation of leukocyte migration from the bloodstream; activation of neutrophils; inflammatory pain; host defence against infection; increased interleukin production and transcription []. It is found in elevated concentrations in a number of inflammatory and allergic conditions, such as asthma, psoriasis, rheumatoid arthritis and inflammatory bowel disease, and has been implicated in the pathogenesis of these diseases [].Binding sites for LTB4 have been observed in membrane preparations from leukocytes, macrophages and spleen. Two receptors for LTB4 have since been cloned (BLT1 and BLT2); both are members of the rhodopsin-like G-protein-coupled receptor superfamily [].The leukotriene B4 type 1 receptor (BLT1) has been cloned from Homo sapiens (Human), Mus musculus (Mouse) and Rattus norvegicus (Rat), and was found to be identical to a previously cloned receptor, P2Y7 [, ]. This receptor was originally thought to be a purinoceptor but is now widely accepted to bind LTB4. BLT1 has also been reported to act as a coreceptor for macrophage-tropic Human immunodeficiency virus 1 (HIV-1) strains []. BLT1 is expressed primarily in peripheral leukocytes and peritoneal macrophages, with lower levels of expression detected in the spleen and thymus of humans []. Activation of the receptor by LTB4 leads to the production of inositol trisphosphate and an increase in intracellular calcium levels. This response is sensitive to pertussis toxin in some cell types. The receptor also causes chemotaxis and inhibition of forskolin-stimulated adenylyl cyclase activity in a pertussis toxin sensitive manner. It has been demonstrated that BLT1 can couple to Gi2 and G16 G-proteins, depending on the cell type in which it is expressed [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, butbetween which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].Leukotrienes (LT) are potent lipid mediators derived from arachidonic acid metabolism. They can be divided into two classes, based on the presence or absence of a cysteinyl group. Leukotriene B4 (LTB4) does not contain such a group, whereas LTC4, LTD4, LTE4 and LTF4 are cysteinyl leukotrienes.LTB4 is one of the most effective chemoattractant mediators known, and is produced predominantly by neutrophils and macrophages. It is involved in a number of events, including: stimulation of leukocyte migration from the bloodstream; activation of neutrophils; inflammatory pain; host defence against infection; increased interleukin production and transcription []. It is found in elevated concentrations in a number of inflammatory and allergic conditions, such as asthma, psoriasis, rheumatoid arthritis and inflammatory bowel disease, and has been implicated in the pathogenesis of these diseases [].Binding sites for LTB4 have been observed in membrane preparations from leukocytes, macrophages and spleen. Two receptors for LTB4 have since been cloned (BLT1 and BLT2); both are members of the rhodopsin-like G-protein-coupled receptor superfamily [].The leukotriene B4 type 2 receptor gene (BLT2) has been located in both the human and mouse genomes, and is found in close proximity to BLT1 in both species []. The receptor is expressed in most human tissues, with highest levels in the liver, spleen, ovary and leukocytes []. Binding of LTB4 to the receptor produces increased levels of inositol trisphosphate and calcium, inhibition of forskolin-stimulated adenylyl cyclase activity and chemotaxis []. These effects may be accomplished by coupling to G-proteins of the Gq, Gi and Gz classes [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. Vasoactive intestinal polypeptide (VIP) has a wide physiological profile.In the periphery, it induces relaxation in smooth muscle; inhibitssecretion in certain tissues, but stimulates secretion in others; andmodulates activity of cells in the immune system. In the CNS, it has arange of both excitatory and inhibitory actions. VIP receptors aredistributed widely in the periphery, and occur throughout the gastrointestinal tract and genitourinary system, other smooth muscles andsecretory glands. In the CNS, they are found abundantly in, e.g. the cortex,hippocampus and thalamus. All VIP receptors activate adenylyl cyclase.There are two structurally distinct receptors that recognise VIP peptidesand pituitary adenylate cyclase activating polypeptide (PACAP) with similaraffinities (PACAP/VIPR-1, PACAP/VIPR-2), as well as a specific receptor forthe PACAP peptide (PACAP-1). RNA transcripts for all three receptor typesare found in human heart, brain and adipose tissue []. VIPR-1 isconstitutively expressed, while the expression of VIPR-2 is induced onlyfollowing stimulation through the TCR-associated CD3 complex []. VIPinduces the expression of the VIPR-2 gene in the absence of additionalstimuli. Differential expression and regulation of the two VIP receptorsin T lymphocytes suggests different physiological roles in mediating theimmunomodulatory activities of VIP and related neuropeptides []. PACAP type I receptors arepresent in the hypothalamus and anterior pituitary, where they regulate therelease of adrenocorticotropin, luteinising hormone, growth hormone andprolactin, and in the adrenal medulla, where they regulate the release ofepinephrine []. The receptors are also found in high concentrations intesticular germ cells, where they may regulate spermatogenesis, and in sometransformed cell lines, such as the rat pancreatic acinar carcinoma cellAR4-2J [].This entry represents VIPR-1.
