Chromosome alignment-maintaining phosphoprotein 1 (CAMP or CHAMP1) is a zinc-finger protein required for maintaining kinetochore-microtubule attachment during bi-orientation. It contains three characteristic repeat motifs termed the WK, SPE, and FPE motifs [].
This family consists of several bacterial CAMP factor (Cfa) proteins, which seem to be specific to Streptococcus species. The CAMP reaction is a synergistic lysis of erythrocytes by the interaction of an extracellular protein (CAMP factor) produced by some streptococcal species with the Staphylococcus aureus sphingomyelinase C (beta-toxin) [].
Transcription initiation is dictated by the presence and activity of specific nuclear factors that bind to DNA regulatory sequences and interact with the transcriptional machinery. The functions of some of these factors can be altered by phosphorylation, which affects both DNA binding and transcriptional activation []. Phosphorylation is effected by specific protein kinases that have been activated by the stimulus of signal transduction pathways, resulting in the regulation of gene transcription by modulating the phosphorylation sites of transcription factors.Cyclic AMP (cAMP) regulates the expression of many genes via a conserved gene promoter element CRE (cAMP response element) [], which has the sequence 5'-TGACGTCA-3' []. The cAMP response element binding protein (CREB) is a nuclear factor that is regulated by protein kinase A phosphorylation. Transcription is stimulated on binding to the CRE of a phosphorylated CREB dimer, which is held together by leucine zippers. Dimerisation and transcriptional efficacy have been found to be stimulated by phosphorylation at several distinct sites, and it has thus been suggested []that CREB may be regulated by multiple kinases. Sequence analysis of the gene has revealed a cluster of protein kinase A, protein kinase C, and casein kinase II consensus recognition sites near the N terminus of the protein sequence, and the proximity of these sites to one another indicates the possibility of interaction in a positive or negative fashion to regulate CREB bioactivity.The 'leucine zipper' is a structure that is believed to mediate the function of several eukaryotic gene regulatory proteins. The zipper consists of a periodic repetition of leucine residues at every seventh position, and regions containing them appear to span 8 turns of α-helix. The leucine side chains that extend from one helix interact with those from a similar helix, hence facilitating dimerisation in the form of a coiled-coil. Leucine zippers are present in many gene regulatory proteins, including the CREB proteins, Jun/AP1 transcription factors, fos oncogene and fos-related proteins, C-myc, L-myc and N-myc oncogenes, and so on.
Phosphodiesterase 4 (PDE4) is a contributor to intracellular signalling and an important drug target. The four members of this family (PDE4A-D) have high selectivity for cAMP [].This entry includes PDE4B.
Neuropeptide S (NPS) is a bioactive peptide that may be involved in several biological processes, including food intake, locomotion, wakefulness, arousal, and anxiety. NPS activates its cognate G protein-coupled receptor (NPSR1) at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP [, , ].
In Schizosaccharomyces pombe the Gti1 protein promotes the onset of gluconate uptake upon glucose starvation []. The Pac2 protein controls the onset of sexual development, by inhibiting the expression of ste11, in a pathway that is independent of the cAMP cascade [].
This domain is found in a diverse range of phosphoesterases [], including bis(5'-nucleosyl)-tetraphosphatase (apaH), nucleotidases, sphingomyelin phosphodiesterases and 2'-3' cAMP phosphodiesterases, as well as nucleases such as bacterial SbcD or archaeal/yeast Mre11. The most conserved regions in this domain centre around the metal chelating residues.
This family includes 3',5'-cyclic adenosine monophosphate phosphodiesterase CpdA, which hydrolyses cAMP to 5'-AMP. It plays an important regulatory role in modulating the intracellular concentration of cAMP, thereby influencing cAMP-dependent processes []. In Pseudomonas is specifically required for regulation of virulence factors and can also hydrolyse cGMP [].
Cyclic-AMP phosphodiesterase () (PDE) catalyses the hydrolysis of cAMP to the corresponding nucleoside 5' monophosphate. On the basis of sequence similarity, most PDEs can be grouped together [], but some enzymes lie apart from the main family and represent a second distinct class []that includes PDEs from Dictyostelium and yeast.This entry contains class-II cyclic-AMP phosphodiesterases.
Adenylate cyclase is the enzyme responsible for the synthesis of cAMP from ATP. On the basis of sequence similarity, it has been proposed that there are three different classes of adenylate cyclases [, ]. Class I cyclases are found in enterobacteria and related Gram-negative bacteria.
Adenylate cyclase is the enzyme responsible for the synthesis of cAMP from ATP. On the basis of sequence similarity, it has been proposed that there are three different classes of adenylate cyclases [, ]. Class I cyclases are found in enterobacteria and related Gram-negative bacteria.This entry represents the N-terminal domain of class-I adenylate cyclases.
ATF3 belongs to the ATF/cAMP-response element-binding protein family. It is a transcriptional activator that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. It serves as a hub in cellular adaptive-response and plays important roles in cancer and immunity [, ].
ATF1, CREB, and CREM constitute a subfamily of the basic leucine zipper transcription factors, and they activate gene expression by binding as homo- or heterodimers to the cAMP response elements (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'). ATF1 (activating transcription factor 1) plays important roles in cell survival and proliferation [, ]. It is required for the development of preimplantation embryos [].
ATF4 belongs to the ATF/cAMP-response element-binding protein family. It is a transcriptional activator that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters [, ]. It plays a crucial role in the adaptation to stresses by regulating the transcription of many genes [].
Escherichia coli induces the synthesis of at least 30 proteins at the onset of carbon starvation, two-thirds of which are positively regulated by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) complex. Proteins in this entry include carbon starvation protein CstA, which is a predicted membrane protein that may be involved in peptide utilisation []. This entry represents the N-terminal domain of CstA.
This entry represents type 10 adenylate cyclases (also known as soluble adenylyl cyclase; ), which produces cAMP and phosphate from ATP. This enzyme has a critical role in mammalian spermatogenesis by producing cAMP to mediate the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis []. This induces capacitation, the maturational process that sperm undergo prior to fertilization. Soluble adenylyl cyclase binds 2 magnesium ions per subunit, and is activated by manganese or magnesium ions. The enzyme is activated by bicarbonate in the presence of magnesium ions, and inhibited by bicarbonate i nthe presence of manganese ions. Genetic variations in the gene that encodes this enzyme (ADCY10) are associated with absorptive hypercalciuria type 2 (HCA2) (OMIM:143870).
This family consists of several mammalian protein kinase A anchoring protein 3 (PRKA3) or A-kinase anchor protein 110kDa (AKAP 110) sequences. Agents that increase intracellular cAMP are potent stimulators of sperm motility. Anchoring inhibitor peptides, designed to disrupt the interaction of the cAMP-dependent protein kinase A (PKA) with A kinase-anchoring proteins (AKAPs), are potent inhibitors of sperm motility. PKA anchoring is a key biochemical mechanism controlling motility. AKAP110 shares compartments with both RI and RII isoforms of PKA and may function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction [].SPHK1-interactor and AKAP domain-containing proteins are proteins that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II). May act as a converging factor linking cAMP and sphingosine signaling pathways. Plays a regulatory role in the modulation of SPHK1 [].
Cyclic nucleotide-binding proteins play a prominent role in cellular signaling. Their activity is regulated by binding of cAMP and/or cGMP to a highly conserved cyclic nucleotide-binding domain (CNBD), consisting of eight beta sheets that are flanked by three alpha helices []. This entry includes cyclic nucleotide-binding domain-containing protein 1/2 (CNBD1/2). Mouse CNBD2, also known as CRIS, plays an important role in spermatogenesis and regulates sperm motility by controlling the development of the flagellar bending of sperm [].
Opalin (oligodendrocytic myelin paranodal and inner loop protein) is a brain specific, single-pass type I membrane protein []. Its function is not clear. In mouse, it is expressed specifically in oligodendrocytes of the brain [, , ]. It is induced by leukemia inhibitory factor (LIF) and cAMP analogs. It is suppressed in the presence of astrocytic or neural-stem-like differentiation factors such as bone morphotic protein (BMP) and fetal calf serum [].
Cyclic-AMP phosphodiesterase () (PDE) catalyses the hydrolysis of cAMP to the corresponding nucleoside 5' monophosphate. On the basis of sequence similarity, most PDEs can be grouped together [], but some enzymes lie apart from the main family and represent a second distinct class []that includes PDEs from Dictyostelium and yeast. In the central part of these enzymes there is a highly conserved site which contains three histidines. This entry represents that conserved site.
cGMP-gated cation channel alpha-1 (CNGA1, also known as CNG1) is a alpha subunit of the cyclic nucleotide-gated (CNG) channel. CNG channels control the influx of Ca2+ and Na+ in response to signal-induced changes of cGMP or cAMP levels. They play a key role in olfactory and visual transduction []. Mutations in the CNGA1 gene cause retinitis pigmentosa 49 (RP49), a retinal dystrophy belonging to the group of pigmentary retinopathies [, ].
Cyclic nucleotide-gated cation channel beta-1 (CNGB1, also known as CNG4 or GARP) is a beta subunit of the cyclic nucleotide-gated (CNG) channel. CNG channels control the influx of Ca2+and Na+ in response to signal-induced changes of cGMP or cAMP levels. They play a key role in olfactory and visual transduction []. CNGB1 has a splice variant known as GARP2, which is a high affinity rod photoreceptor phosphodiesterase (PDE6)-binding protein that modulates its catalytic properties [].
Cyclic nucleotide-gated cation channel beta-3 (CNGB3, also known as CNG6) is a beta subunit of the cyclic nucleotide-gated (CNG) channel. CNG channels control the influx of Ca2+ and Na+ in response to signal-induced changes of cGMP or cAMP levels. They play a key role in olfactory and visual transduction []. Mutations in the CNGB3 gene have been linked to achromatopsia (rod monochromacy, total colour blindness) [].
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 [].It has been suggested that the cAMP receptors coordinate aggregation ofindividual cells into a multicellular organism, and regulate the expressionof a large number of developmentally-regulated genes [, , ]. The amino acidsequences of the receptors contain high proportions of hydrophobic residuesgrouped into 7 domains, in a manner reminiscent of the rhodopsins and otherreceptors believed to interact with G-proteins. However, while a similar3D framework has been proposed to account for this, there is no significantsequence similarity between these families: the cAMP receptors thus beartheir own unique '7TM' signature.
PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium acting via calmodulin) [, ]. PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2 binding motifs referred to as EF hands [].
Protozoan pheromones are cell-type specific protein signals. This entry represents the mating ciliate pheromone (or gamone) Er-23 from the protozoan Euplotes raikovi. Er-23 is a diffusible extracellular communication signal that distinguishes different intra-specific classes of cells commonly referred to as 'mating types'. Er-23 prepares these cells for conjugation by changing its cell surface properties. The mitogenic activity induced by the Er pheromone autocrine signalling can be inhibited by cAMP []. The NMR structure of Er-23 reveals an all-alpha topology that is rich in disulphide bonds []. In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
Protozoan pheromones are cell-type specific protein signals. This entry represents the mating ciliate pheromones (or gamones) Er-2 and Er-23 from the protozoan Euplotes raikovi. These pheromones are diffusible extracellular communication signals that distinguishes different intra-specific classes of cells commonly referred to as 'mating types'. Pheromones prepare these cells for conjugation by changing their cell surface properties. The mitogenic activity induced by the Er pheromone autocrine signalling can be inhibited by cAMP []. The NMR structures of Er-2 and Er-23 reveal an all-alpha orthogonal bundle topology [, ]. In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
This entry represents the 7TM domain found in histamine H3 receptor (HRH3 or H3R), which belongs to the class A of GPCRs. Histamine plays a key role as chemical mediator and neurotransmitter in various physiological and pathophysiological processes in the central and peripheral nervous system. Histamine exerts its functions by binding to four different G protein-coupled receptors (H1-H4). The H3 and H4 receptors couple to the G(i)-proteins, which leading to the inhibition of cAMP formation []. The H3R receptor functions as a presynaptic autoreceptors controlling histamine release and synthesis []. The H4R plays an important role in histamine-mediated chemotaxis in mast cells and eosinophils [].
This entry includes a group of cyclic nucleotide phosphodiesterases, including GpdQ and CpdA. They belong to the metallophosphatase (MPP) superfamily.GpdQ (glycerophosphodiesterase Q, also known as Rv0805 in Mycobacterium tuberculosis) is a binuclear metallophosphoesterase from Enterobacter aerogenes that catalyzes the hydrolysis of mono-, di-, and triester substrates, including some organophosphate pesticides and products of the degradation of nerve agents []. The GpdQ homologue, Rv0805, has 2',3'-cyclic nucleotide phosphodiesterase activity [].CpdA hydrolyses cAMP to 5'-AMP. It plays an important regulatory role in modulating the intracellular concentration of cAMP, thereby influencing cAMP-dependent processes []. In Pseudomonas is specifically required for regulation of virulence factors and can also hydrolyse cGMP [].
Adhesion G-protein coupled receptor V1 (ADGRV1), also known as G protein-coupled receptor 98, is a receptor that has an essential role in the development of hearing and vision [, , , ]. It couples to G-alpha(i)-proteins, GNAI1/2/3, G-alpha(q)-proteins, GNAQ, as well as G-alpha(s)-proteins, GNAS, inhibiting adenylate cyclase (AC) activity and cAMP production [, ]. Defects in GPR98 are the cause of Usher syndrome type 2C (USH2C). USH is a genetically heterogeneous condition characterised by the association of retinitis pigmentosa with sensorineural deafness [, ]. Defects in GPR98 may also be a cause of familial febrile convulsions type 4 (FEB4); also known as familial febrile seizures 4 [].
Adenylate cyclase is the enzyme responsible for the synthesis of cAMP from ATP. From sequence data, it has been proposed that there are three different classes of adenylate cyclases [, ]. Class I cyclases are found in enterobacteria and related Gram-negative bacteria. They are proteins of about 850 residues that consist of two functional domains: a N-terminal catalytic domain and a C-terminal regulatory domain.There are two highly conserved regions, the first one is located in the catalytic domain and the second one in the regulatory domain. The second signature includes a conserved histidine which could be phosphorylated by a PTS system IIA enzyme, thus leading to the activation of the cyclase.
DH31 is a diuretic hormone that increases cAMP production and fluid secretion in Malpighian tubules of several insect species. DH31 is similar to the calcitonin family [, ]. In Drosophila, it has also been linked to a neuropeptide relay mechanism for circadian control of sleep [], and peristalsis in the junction region of the larval midgut []. Drosophila neuropeptide DH31 is a ligand for orphan GPCR named CG17415 [].This entry also includes venom protein 55.1 and U-limacoditoxin(8)-Dv66 (also known as Vulnericin) [], which belong to the diuretic hormone class 2 family.
This entry represents proteins from various mammals known as DEPP proteins, which are decidual proteins induced by progesterone.Decidualization of the endometrial stromal cells (ESC) is thought to be stimulated by progesterone and/or cAMP and is crucial for embryo implantation and placentation. Increased expression of Depp was observed in endometria during mid- and late-secretory phases and 1st trimester deciduas. Depp increased the level of phosphorylated Erk and activated the Elk-1 transcription factor in human embryonal kidney 293 cells, suggesting that Depp modulates the effects of progesterone during decidualization and in the decidua by affecting gene expression [].
This family consists of several glucitol operon activator (GutM) proteins. Expression of the glucitol (gut) operon in Escherichia coli is regulated by an unusual, complex system, which consists of an activator (encoded by the gutM gene) and a repressor (encoded by the gutR gene) in addition to the cAMP-CRP complex (CRP, cAMP receptor protein). Synthesis of the mRNA, which initiates at the promoter specific to the gutR gene, occurs within the gutM gene. Expressional control of the gut operon appears to occur as a consequence of the antagonistic action of the products of the autogenously regulated gutM and gutR genes [].
Anoctamin-1 (Ano1, also known as TMEM16A) is a calcium-activated chloride channel (CaCC) that plays a role in multiple physiological functions [, ]. It is a heat sensor that mediates thermal pain in sensory neurons []. It is responsible for most of the iodide efflux across the apical membrane of thyroid cells []. It contributes to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells []. It is expressed in the airway epithelium for controlling mucin-secretion [], in the blood vessels for vascular tone [], and in the pacemaker cells for gastrointestinal smooth muscle contraction [].
This family consists of several mammalian protein kinase A anchoring protein 3 (PRKA3) or A-kinase anchor protein 110kDa (AKAP 110) sequences. Agents that increase intracellular cAMP are potent stimulators of sperm motility. Anchoring inhibitor peptides, designed to disrupt the interaction of the cAMP-dependent protein kinase A (PKA) with A kinase-anchoring proteins (AKAPs), are potent inhibitors of sperm motility. PKA anchoring is a key biochemical mechanism controlling motility. AKAP110 shares compartments with both RI and RII isoforms of PKA and may function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction [].
Praja-2 belongs to the mammalian RING E3-ubiquitin ligase family and has E2-dependent E3 ubiquitin-protein ligase activity. It regulates the total concentration of protein kinase A (PKA) regulatory (Rs) subunits, tuning the strength and duration of PKA signal output in response to cAMP []. It binds to MOB1 (Mps one binder 1), a core effector of the Hippo pathway, and serves as an upstream regulator of the Hippo signalling, linking the ubiquitin proteasome system to deregulated glioblastoma growth []. Induces the ubiquitination of MFHAS1, which positively regulates the Toll-like receptor 2 signaling/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-kB pathway and promotes the polarization of macrophages toward the pro-inflammatory M1 phenotype [].
cAMP-responsive element-binding protein 1 (CREB1) is a phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters [, ]. CRE has the sequence 5'-TGACGTCA-3' []. Transcription is stimulated on binding to the CRE of a phosphorylated CREB dimer, which is held together by leucine zippers.CREB1 plays a key role in neural development [, ]. CREB1 signaling pathway can influence mood, addiction, learning and memory by activating an array of proteins [].
Antigen (Ag) recognition by the T cell receptor (TCR) induces activation ofT lymphocytes. However, TCR-mediated signals alone are insufficient forefficient T cell activation, and additional co-stimulatory signals are required. One of the most important surface molecules that delivers co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 (Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of themajority of human peripheral T cells and lymphocytes. Stimulation of CD4+ Tcells in the absence of CD28 co-signalling causes impaired proliferation, reduced cytokine production and altered generation of helper T cell subsets.Co-stimulation via CD28 promotes T cell viability, clonal expansion,cytokine production and effector functions, while also regulating apoptosisof activated T cells, suggesting its importance in regulating long-term T cell survival [, , , ].Ligands for CD28 and the structurally related CTLA-4 (CD152) are themolecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed onprofessional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligandsresults in tyrosine phosphorylation at a YMNM motif within its cytoplasmictail. The phosphorylated motif subsequently interacts with the Src homology2 domain in the p85 regulatory subunit of P13K, activating the p110 catalytic subunit. One of the P13K-dependent downstream targets, resulting from the antibody cross-linking of CD28, is the phoshporylation and activation of Akt (or PKB). Constitutively active Akt is able to substitutefor CD28 signals, and stimulates IL-2 production when introduced into matureCD28-deficient cells. Another molecule affected by CD28 stimulation is theproto-oncogene Vav, which acts as a guanine-nucleotide exchange factor forRac and CDC42, allowing these molecules to switch from the inactive GDP-bound state to the active GTP-bound state [, ].Another interesting feature of CD28, is its ability to induce expression ofPDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP hasbeen reported to affect nearly every pathway important for lymphocyteactivation, leading to inhibition of T cell proliferation. Specifically,increased intracellular cAMP has been implicated in the induction of T cellanergy, a non-responsive state that occurs after T cells are stimulatedthrough TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundlyimmunosuppressive, preventing induction of pathogenic T cell responses inautoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation []. Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integratesmitogenic MEK and P13K-dependent signals from both TCR and CD28 [].
This family consists of several mammalian protein kinase A anchoring protein 3 (PRKA3) or A-kinase anchor protein 110kDa (AKAP 110) sequences. Agents that increase intracellular cAMP are potent stimulators of sperm motility. Anchoring inhibitor peptides, designed to disrupt the interaction of the cAMP-dependent protein kinase A (PKA) with A kinase-anchoring proteins (AKAPs), are potent inhibitors of sperm motility. PKA anchoring is a key biochemical mechanism controlling motility. AKAP110 shares compartments with both RI and RII isoforms of PKA and may function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction [].This entry represents a sub group of the A-kinase anschor 110kDa protein.
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [], Sildenafil for erectile dysfunction []and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.
Glycoprotein hormone receptors are members the rhodopsin-like G-protein coupled receptor (GPCR) family. They function as receptors for the pituitary hormones thyrotropin (TSH receptor), follitropin (FSH receptor) and lutropin (LH receptor). In mammals the LH receptor is also the receptor for the placental hormone, human chorionic gonadotropin (hCG), so is denominated as a lutropin-choriogonadotropic hormone receptor (LHCG receptor). The receptors share close sequence similarity, and are characterised by large extracellular domains believed to be involved in hormone binding via leucine-rich repeats (LRR) [].This entry represents the thyrotropin receptor, also known as thyroid-stimulating hormone receptor (TSHR) is synthesised in the thyrotroph cells of the anterior pituitary under the influence of TSH and thyroid hormones [, ]. Upon binding circulating thyrotropin, a G-protein signal cascade activates adenylyl cyclase and intercellular levels of cAMP rise. cAMP activates all functional aspects of the thyroid cell, including iodine pumping; thyroglobulin synthesis, iodination, endocytosis and proteolysis; thyroid peroxidase activity; and hormone release [, ]. Graves disease is caused by stimulatory anti-TSH receptor antibodies [, ].
RmlC (deoxythymidine diphosphates-4-dehydrorhamnose 3,5-epimerase; ) is a mainly beta class protein with a jelly roll-like topology. It is a dTDP-sugar isomerase enzyme involved in the synthesis of L-rhamnose, a saccharide required for the virulence of some pathogenic bacteria []. This entry represents the domain with the jelly roll-like fold. Other protein families containing this domain include glucose-6-phosphate isomerase (); germin, a metal-binding protein with oxalate oxidase and superoxide dismutases activities []; auxin-binding protein []; seed storage protein 7S []; acireductone dioxygenase []; as well as three proteins that have metal-binding sites similar to that of germine, namely quercetin 2,3-dioxygenase () [], phosphomannose isomerase () []and homogentisate dioxygenase () [], the last three sharing a 2-domain fold with storage protein 7s.The cAMP-binding domains found in the cAMP receptor protein (CRP) family display a similar β-roll architecture consisting of eight antiparallel β-strands and three helical segments []. These proteins include CooA, a CO-sensing haem protein that functions as a transcription activator [], and the CnbD (cyclic nucleotide binding domain) of the HCN cation channel in which cAMP binding modulates gating of the channel [].
Heterotrimeric G protein-mediated signalling via activated 7-transmembrane (7TM) serpentine receptors is well known in a range of organisms, but evidence for the existence of this pathway in plants has been elusive. Over the years, however, evidence that G proteins are involved in signal transduction in plants has been accumulating, leading several researchers to seek plant 7TM receptors. The first tangible evidence for a plant 7TM receptor came through an analysis of the expresssed sequence tag database, dbEST. This revealed an Arabidopsis thaliana gene (GCR1) that encodes a protein with 7 predicted TM domains, and other features characteristic of known 7TM receptors [, ]. The amino acid sequence of GCR1, however, is unusual in that it shows similarity to receptors from three different 7TM families [, ], sharing greatest levels of similarity with the Dictyostelium cAMP receptors. It has been suggested that the cAMP receptors coordinate aggregation of individual cells into a multicellular organism, and regulate the expression of a large number of developmentally-regulated genes [, , ]. GCR1 is expressed at low levels in the roots, stems and leaves of Arabidopsis. Studies using transgenic Arabidopsis have suggested a functional role for GCR1 in cytokinin signal transduction [].
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [], Sildenafil for erectile dysfunction []and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This entry represents the C-terminal catalytic domain superfamily of PDE which is multihelical and can be divided into three subdomains.
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [], Sildenafil for erectile dysfunction []and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated,playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This domain is found to the N terminus of the calcium/calmodulin-dependent 3'5'-cyclic nucleotide phosphodiesterase domain ().
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [], Sildenafil for erectile dysfunction []and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This region is found at the N terminus of members of PDE8 phosphodiesterase family []. Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes [].
Protozoan pheromones are cell-type specific protein signals. This entry represents the mating ciliate pheromone (or gamone) Er-1 from the protozoan Euplotes raikovi. Er-1 is a diffusible extracellular communication signal that distinguishes different intra-specific classes of cells commonly referred to as 'mating types'. Er-1 prepares these cells for conjugation by changing its cell surface properties. Er-1 exists as membrane-bound and secreted forms, where the membrane-bound form promotes inter-cellular communication and adhesion for mating pair formation and may act as binding site for the secreted form. The mitogenic activity induced by the Er pheromone autocrine signalling can be inhibited by cAMP []. The NMR structure of Er-1 reveals an all-alpha orthogonal bundle topology [, ]. In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.All of these forms contain a catalytic domain of approximately 270 amino acids at the carboxyl terminus. Regulatory domains that vary widely among the PDEase subfamilies flank the catalytic core and include regions that autoinhibit the catalytic domains as well as targeting sequences that control subcellularlocalization [].PDEase catalytic domains adopt a compact α-helical structure consisting of 16 α-helices that can be divided into three subdomains. The active site of PDEases is a deep pocket formed by the three subdomains and can be divided into two major subpockets for binding of divalent metals and substrate/inhibitors, respectively. The active site of all PDEase domains contains two divalent metal ions: zinc and probably magnesium [, , ].
Protozoan pheromones are cell-type specific protein signals. This entry represents a superfamily of mating ciliate pheromones (or gamones) from the protozoan Euplotes raikovi, including Er-1, Er-2, Er-10, Er11 and Er22. These pheromones are diffusible extracellular communication signals that distinguish different intra-specific classes of cells commonly referred to as 'mating types'. Pheromones prepare these cells for conjugation by changing their cell surface properties. The mitogenic activity induced by Er pheromone autocrine signalling can be inhibited by cAMP []. The NMR structure of several pheromones have been determined, revealing a closed up-and-down bundle of three helices with a left-handed twist [, , , , ]. In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
Protozoan pheromones are cell-type specific protein signals. This entry represents a family of mating ciliate pheromones (or gamones) from the protozoan Euplotes raikovi, including Er-1, Er-2, Er-10, Er11 and Er22. These pheromones are diffusible extracellular communication signals that distinguish different intra-specific classes of cells commonly referred to as 'mating types'. Pheromones prepare these cells for conjugation by changing their cell surface properties. The mitogenic activity induced by Er pheromone autocrine signalling can be inhibited by cAMP []. The NMR structure of several pheromones have been determined, revealing a closed up-and-down bundle of three helices with a left-handed twist [, , , , ]. In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.
The Spot 14 family includes thyroid hormone-inducible hepatic protein (Spot 14), Mid1-interacting protein and related sequneces. Mainly expressed in tissues that synthesise triglycerides, the mRNA coding for Spot 14 has been shown to be increased in rat liver by insulin, dietary carbohydrates, glucose in hepatocyte culture medium, as well as thyroid hormone. In contrast, dietary fats and polyunsaturated fatty acids, have been shown to decrease the amount of Spot 14 mRNA, while an elevated level of cAMP acts as a dominant negative factor. In addition, liver-specific factors or chromatin organisation of the gene have been shown to contribute to the regulation of its expression []. Spot 14 protein is thought to be required for induction of hepatic lipogenesis []. Mid1-interacting protein is involved in stabilisation of microtubules [].
Pituitary adenylate cyclase-activating polypeptide (PACAP) plays important roles in the control of immunity and inflammation, pancreatic insulin secretion, release of catecholamines from the adrenal medulla, neurogenesis and neurotransmitter release [, ]. It exerts its actions through three G protein-coupled receptors (GPCRs): the PACAP-specific PAC1-R, which is coupled to several transduction systems, and the PACAP/VIP receptors VPAC1-R and VPAC2-R, which are primarily coupled to adenylyl cyclase []. PACAP is widely distributed in the brain and peripheral organs. It is expressed in sympathetic neurons and in the cholinergic innervation of the adrenal medulla, where it is thought to facilitate secretion of catecholamines under conditions of high stress []. In pancreatic islets PACAP stimulates insulin and glucagon secretion, in part through increased formation of cAMP after activation of adenylate cyclase and in part through increase in cytosolic calcium [].
The TerD domain is found in TerD family proteins that include the paralogous TerD, TerA, TerE, TerF and TerZ proteins [, ]. It is found in a stress response operon with TerB and TerC. TerD has a maximum of two calcium binding sites [, ]depending on the conservation of aspartates []. It has various fusions to nuclease domains, RNA binding domains, ubiquitin related domains, and metal binding domains. The ter gene products lie at the centre of membrane-linked metal recognition complexes with regulatory ramifications encompassing phosphorylation-dependent signal transduction, RNA-dependent regulation, biosynthesis of nucleoside-like metabolites and DNA processing linked to novel pathways [].TerD domain is also found in cAMP binding protein, chemical-damaging agent resistance proteins and general stress proteins. The cellular Slime mould, Dictyostelium discoideum, contains a cAMP-binding protein, CABP1, which is composed of two subunits. The C-terminal half of these subunits contain this domain [].
This entry represents the RING-like U-box domain found in E3 ubiquitin-protein ligase CHIP and LubX.CHIP is a multifunctional protein that functions both as a co-chaperone and an E3 ubiquitin-protein ligase. It couples protein folding and proteasome mediated degradation by interacting with heat shock proteins (e.g. HSC70) and ubiquitinating their misfolded client proteins thereby targeting them for proteasomal degradation [, ]. It is also important for cellular differentiation and survival (apoptosis), as well as susceptibility to stress. It targets a wide range of proteins, such as expanded ataxin-1, ataxin-3, huntingtin, and androgen receptor, which play roles in glucocorticoid response, tau degradation, and both p53 and cAMP signaling [, ]. LubX is an E3 ubiquitin ligase that interferes with host's ubiquitination pathway. LubX contains two U-box domains and was shown to interact with a diverse group of mammalian E2-conjugating enzymes including UBE2W, UBEL6, and members of the UBE2D and UBE2E families to direct ubiquitination of mammalian Cdc2-like kinase 1 (Clk1) [, ].
SNX14 (sorting nexin-14) is expressed in the embryonic nervous system of mammals such as mice, being co-expressed with homoprotein islet-1 in several tissues []. SNX14 levels increase progressively during neuronal development and its knockdown impairs both excitatory and inhibitory synaptic transmission, suggesting a role in neuronal development and function []. SNX14 contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal PXC domain []. Its RGS domain is non-functional as a GTPase activator for Galpha, but it binds to and sequesters Galpha, thus inhibiting downstream cAMP production [].This entry represents the PX domain of SNX14. The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions [, ].
MSK1/2 (Mitogen and Stress-induced Kinase, also known as RSKB) are partially redundant serine/threonine kinases that are phosphorylated downstream of MAPK (Erk and/or p38-mediated) and cAMP signal transduction pathways []. They phosphorylate multiple substrates, including CREB and Histone H3 and regulate specific subsets of Immediate Early genes (IEG) []. They are involved in limiting inflammation in innate immunityand is implicated in neurodegeneration and synaptic plasticity []. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family, similar to 90kDa ribosomal protein S6 kinases (RSKs) []. This entry represents the N-terminal catalytic domain of MSK2. MSK2 is also known as ribosomal protein S6 kinase alpha-4 (RPS6KA4).
3'5'-cyclic nucleotide phosphodiesterases () (PDEases) catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates []. There are at least seven different subfamilies of PDEases []: Type 1, calmodulin/calcium-dependent PDEases. Type 2, cGMP-stimulated PDEases. Type 3, cGMP-inhibited PDEases. Type 4, cAMP-specific PDEases. Type 5, cGMP-specific PDEases. Type 6, rhodopsin-sensitive cGMP-specific PDEases. Type 7, High affinity cAMP-specific PDEases. All of these forms seem to share a conserved domain of about 270 residues. This entry has a signature pattern from a stretch of 12 residues that contains two conserved histidines. The PDEase catalytic domains adopt a compact α-helical structureconsisting of 16 α-helices that can be divided into three subdomains. The active site of PDEases is a deep pocket formed by the treesubdomains and can be divided into two major subpockets for binding ofdivalent metals and substrate/inhibitors, respectively. The active site of allPDEase domains contains two divalent metal ions: zinc and probably magnesium[, , ].
This entry represents a group of E3 ubiquitin-protein ligases, including CHIP from eukaryotes and LubX from bacteria. CHIP is a multifunctional protein that functions both as a co-chaperone and an E3 ubiquitin-protein ligase. It couples protein folding and proteasome mediated degradation by interacting with heat shock proteins (e.g. HSC70) and ubiquitinating their misfolded client proteins thereby targeting them for proteasomal degradation [, ]. It is also important for cellular differentiation and survival (apoptosis), as well as susceptibility to stress. It targets a wide range of proteins, such as expanded ataxin-1, ataxin-3, huntingtin, and androgen receptor, which play roles in glucocorticoid response, tau degradation, and both p53 and cAMP signaling [, ]. LubX is an E3 ubiquitin ligase that interferes with host's ubiquitination pathway. LubX contains two U-box domains and was shown to interact with a diverse group of mammalian E2-conjugating enzymes including UBE2W, UBEL6, and members of the UBE2D and UBE2E families to direct ubiquitination of mammalian Cdc2-like kinase 1 (Clk1) [, ].
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 [, , ].This entry represents the seven transmembrane regions of the G-protein coupled receptor 176 (GPCR176), a member of the rhodopsin-like class A GPCR superfamily. Its endogenous ligand has not yet been identified. It is highly expressed in suprachiasmatic nucleus (SCN) neurons in a circadian rhythm manner, which has a role in setting the pace of the circadian behaviour. This receptor has an agonist-independent basal activity to reduce cAMP signalling and it has been shown that it acts through a unique G-protein subclass Gz to repress the second messenger signalling [, ].
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 [, , ].Psychosine is a glycosphingolipid implicated in the pathology of globoidcell leukodystrophy (GLD), a hereditary metabolic disorder that results fromthe absence of the enzyme galactosyl ceramide. This deficiency results inthe accumulation of psychosine in the brain, leading to apoptosis ofoligodendrocytes, progressive demyelination and the existence of large,multinuclear cells (globoid cells) derived from microglia []. The molecular mechanism by which these toxic effects might be mediated hasrecently been elucidated by the identification of TDAG8, an orphan Gprotein-coupled receptor, as a receptor for psychosine []. TDAG8 isexpressed at high levels in the spleen, peripheral blood leukocytes, lymphnodes and lung. Activation of the receptor in RH7777 hepatoma cells bypsychosine and related lysoglycolipids results in a pertussis toxin-insensitive inhibition of forskolin-induced cAMP accummulation, possibly through coupling to Gz 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 [, , ].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.Prostaglandin E2 receptor EP2, also called prostanoid EP2 receptor, is one of fourreceptor subtypes whose endogenous physiological ligand is prostaglandin E2 (PGE2). Stimulation of the EP2 receptor by PGE2 causes cAMP accumulation through G(s) protein activation, which subsequently produces smooth muscle relaxation and mediates the systemic vasodepressor response to PGE2.
The crp-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 70-75 amino acids present in transcription regulators of the crp-fnr family, involved in the control of virulence factors, enzymes of aromatic ring degradation, nitrogen fixation, photosynthesis, and various types of respiration. The crp-fnr family is named after the first members identified in Escherichia coli: the well characterised cyclic AMP receptor protein CRP or CAP (catabolite activator protein) and the fumarate and nitrate reductase regulator Fnr. crp-type HTH domain proteins occur in most bacteria and in chloroplasts of red algae. The DNA-binding HTH domain is located in the C-terminal part; the N-terminal part of the proteins of the crp-fnr family contains a nucleotide-binding domain and a dimerisation/linker helix occurs in between. The crp-fnr regulators predominantly act as transcription activators, but can also be important repressors, and respond to diverse intracellular and exogenous signals, such as cAMP, anoxia, redox state, oxidative and nitrosative stress, carbon monoxide, nitric oxide or temperature []. The structure of the crp-type DNA-binding domain shows that the helices (H) forming the helix-turn-helix motif (H2-H3) are flanked by two β-hairpin (B) wings, in the topology H1-B1-B2-H2-H3-B3-B4. Helix 3 is termed the recognition helix, as in most wHTHs it binds the DNA major groove [, , ]. Some proteins known to contain a Crp-type HTH domain: E. coli crp (also known as cAMP receptor), a protein that complexes with cAMP and regulates the transcription of several catabolite-sensitive operons. E. coli fnr, a protein that activates genes for proteins involved in a variety of anaerobic electron transport systems. Rhizobium leguminosarum fnrN, a transcription regulator of nitrogen fixation. Rhodobacter sphaeroides (Rhodopseudomonas sphaeroides) fnrL, a transcription activator of genes for heme biosynthesis, bacteriochlorophyll synthesis and the light-harvesting complex LHII. Rhizobiacae fixK, a protein that regulates nitrogen fixation genes, both positively and negatively. Lactobacillus casei fnr-like protein flp, a putative regulatory protein linked to the trpDCFBA operon. Cyanobacteria ntcA, a regulator of the expression of genes subject to nitrogen control. Xanthomonas campestris clp, a protein involved in the regulation of phytopathogenicity. Clp controls the production of extracellular enzymes, xanthan gum and pigment, either positively or negatively.
Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues [, , ]. The best studied of these proteins is the prokaryotic catabolite gene activator (alsoknown as the cAMP receptor protein) (gene crp) where such a domain is known to be composed of three α-helices and a distinctive eight-stranded, antiparallel β-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the β-barrel. cAMP- and cGMP-dependent protein kinases (cAPK and cGPK) contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chain and a regulatory chain,which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterised, one is found in rod cells where it plays a role in visual signal transduction.
Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues [, , ]. The best studied of these proteins is the prokaryotic catabolite gene activator (alsoknown as the cAMP receptor protein) (gene crp) where such a domain is known to be composed of three α-helices and a distinctive eight-stranded, antiparallel β-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the β-barrel. cAMP- and cGMP-dependent protein kinases (cAPK and cGPK) contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chain and a regulatory chain,which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterised, one is found in rod cells where it plays a role in visual signal transduction.
Calcitonin []is a 32 amino acid polypeptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in the blood, by promoting the incorporation of these ions in the bones. This is the alpha type. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. CGRP induces vasodilatation in a variety of vessels, including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.Islet amyloid polypeptide (IAPP) [](also known as diabetes-associated peptide (DAP), or amylin) is a peptide of 37 amino acids that selectively inhibits insulin-stimulated glucose utilisation and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Structurally, IAPP is closely related to CGRP.Calcitonin receptor-stimulating peptide 1 stimulates cAMP production via the calcitonin receptor.Two conserved cysteines in the N-terminal of these peptides are known to be involved in a disulphide bond. The C-terminal residue of all three peptides is amidated.xCxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxx-NH(2)| | Amide group+-----+'C': conserved cysteine involved in a disulphide bond.
The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in guanylyl cyclases and phytochromes [, ]. The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain []. Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively, these products up-regulating catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding. Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region [].The GAF domain is also found in FhlA (formate hydrogen lyase transcriptional activator) and NifA, a transcriptional activator required for activation of most Nif operons, which are directly involved in nitrogen fixation. NifA interacts with sigma-54 [].
PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium and calmodulin). PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy, and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2+ binding motifs referred to as EF hands [].The PPP (phosphoprotein phosphatase) family, to which PP2B belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes [, ]. PPPs belong to the metallophosphatase (MPP) superfamily.
5-hydroxytryptamine (5-HT) or serotonin, is a neurotransmitter that it is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS). It is implicated in a vast array of physiological and pathophysiological pathways. Receptors for 5-HT mediate both excitatory and inhibitory neurotransmission, and modulate the release of many neurotransmitters including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin and cortisol. In the CNS, 5-HT receptors can influence various neurological processes, such as aggression, anxiety and appetite and, as a, result are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics and anorectics []. The 5-HT receptors are grouped into a number of distinct subtypes, classified according to their antagonist susceptibilities and their affinities for 5-HT. With the exception of the 5-HT3 receptor, which is a ligand-gated ion channel [], all 5-HT receptors are members of the rhodopsin-like G protein-coupled receptor family [], and they activate an intracellular second messenger cascade to produce their responses. This entry represents the 5-HT5A receptor, which couples to G proteins and negatively influences cAMP []. It has also been shown to function, in part, through the regulation of intracellular Ca2+ mobilisation []. In the CNS, the 5-HT5A receptor is found in the cerebral cortex, hippocampus, habenula, olfactory bulb and granular layer of the cerebellum [, , ]. It may play a role in sleep []and serve as an presynaptic serotonin autoreceptor [].
Structural domains comprising this superfamily share the structure of two shown to be homologous GTPase activating proteins for Rap and Ran. Both are Ras-like guanine-nucleotide-binding proteins (GNBPs) involved in a variety of signal-transduction processes and their activity is regulated by GEFs and GAPs.Rap small G proteins have been implicated in various cellular processes such as exocytosis, cAMP signalling, cell adhesion and cell proliferation. Rap proteins acts as molecular switches, with an active GTP-bound form and an inactive GDP-bound form []. The inactive GDP bound form is promoted by GTPase-activating proteins (GAPs). GAP proteins specific for Rap contain a conserved region of around 200 amino-acid residues, the RapGAP domain. This domain can accelerate the GTP hydrolysis activity of Rap by five orders of magnitude [].Ran, also known as GTP-binding nuclear protein, is on the other hand essential for the translocation of RNA and proteins through the nuclear pore complex and has been implicated in the control of DNA synthesis and cell cycle progression. Proteins known to contain a Rap-GAP domain include:RAP1 GTPase activating protein (RAP1GAP).Mammalian tuberin protein, the product of a familial tuberous sclerosis gene which, when deleted, causes begnin tumours. It also have a GAPactivity for Rab5 [].Drosophila Gigas protein, an homologue of tuberin involved in regulation of cell cycle.Mammalian tuberin-like protein TULIP.GTPase-activating protein Spa-1. It functions as a negative regulator for the activation of Rap1, thereby having a negative effect on cell adhesion[].
Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family []. They participate in differentiation and growth of diverse cell types. Inhibin inhibits secretion of follicle-stimulating hormone by the pituitary []. Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits. Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains. Follistatin is bound to inhibin and activin and indirectly modulates the FSH release. In turn, FSH stimulates inhibin gene expression in the ovarian follicle [], probably mediated by cAMP []. The serum levels of inhibin, activin, and follistatin are elevated in pregnant women and decrease after delivery []. Genes coding for mouse activin beta C and beta E are closely linked and exhibit a liver-specific expression pattern in adult tissues.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions (including various autocrine, para-crine and endocrine processes). They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups. We use the term clan 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 the rhodopsin-like GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating pheromone receptors, and the metabotropic glutamate receptor family. The rhodopsin-like GPCRs themselves 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 [, , ]. A cluster of four intronless GPCR genes, sharing significant sequence similarity with one another, have been identified on human chromosome 19q13.1, downstream from the CD22 gene []. The receptors have been named GPR40, GPR41, GPR42 and GPR43. The GPR42 protein sequence shares more than 98% amino acid identity with GPR41 and is located on a possible polymorphic insert[].
Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues [, , ]. The best studied of these proteins is the prokaryotic catabolite gene activator (alsoknown as the cAMP receptor protein) (gene crp) where such a domain is known to be composed of three α-helices and a distinctive eight-stranded, antiparallel β-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the β-barrel. cAMP- and cGMP-dependent protein kinases (cAPK and cGPK) contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chainand a regulatory chain,which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterised, one is found in rod cells where it plays a role in visual signal transduction.
Calcitonin []is a 32 amino acid polypeptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in the blood, by promoting the incorporation of these ions in the bones. This is the alpha type. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. CGRP induces vasodilatation in a variety of vessels, including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.Islet amyloid polypeptide (IAPP) [](also known as diabetes-associated peptide (DAP), or amylin) is a peptide of 37 amino acids that selectively inhibits insulin-stimulated glucose utilisation and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Structurally, IAPP is closely related to CGRP.Calcitonin receptor-stimulating peptide 1 stimulates cAMP production via the calcitonin receptor.Two conserved cysteines in the N-terminal of these peptides are known to be involved in a disulphide bond. The C-terminal residue of all three peptides is amidated.xCxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxx-NH(2)| | Amide group+-----+'C': conserved cysteine involved in a disulphide bond.
Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family []. They participate in differentiation and growth of diverse cell types. Inhibin inhibits secretion of follicle-stimulating hormone by the pituitary []. Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits. Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains. Follistatin is bound to inhibin and activin and indirectly modulates the FSH release. In turn, FSH stimulates inhibin gene expression in the ovarian follicle [], probably mediated by cAMP []. The serum levels of inhibin, activin, and follistatin are elevated in pregnant women and decrease after delivery []. Genes coding for mouse activin beta C and beta E are closely linked and exhibit a liver-specific expression pattern in adult tissues.This entry represents inhibin beta A subunit.
Heterotrimeric G protein-mediated signalling via activated 7-transmembrane (7TM) serpentine receptors is well known in a range of organisms, but evidence for the existence of this pathway in plants has been elusive. Over the years, however, evidence that G proteins are involved in signal transduction in plants has been accumulating, leading several researchers to seek plant 7TM receptors. The first tangible evidence for a plant 7TM receptor came through an analysis of the expresssed sequence tag database, dbEST. This revealed an Arabidopsis thaliana gene (GCR1) that encodes a protein with 7 predicted TM domains, and other features characteristic of known 7TM receptors [, ]. The amino acid sequence of GCR1, however, is unusual in that it shows similarity to receptors from three different7TM families [, ], sharing greatest levels of similarity with the Dictyostelium cAMP receptors. GCR1 is expressed at low levels in the roots, stems and leaves of Arabidopsis. Studies using transgenic Arabidopsis have suggested a functional role for GCR1 in cytokinin signal transduction [].
The intracellular second messenger cyclic adenosine monophosphate (cAMP) exerts many of its physiological effects by activating cAMP-dependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. PKA is a tetrameric enzyme composed of a two regulatory (R) and two catalytic (C) subunits. Binding of 2 cAMP molecules to each R subunit leads to holoenzyme dissociation into the R dimer and two active subunits [, , ]. There are 4 different R sububits divided in two types, type I (RI-alpha and RI-beta), and type II (RII-alpha and RII-beta), and two main C subunits (C-alpha and C-beta) []. Type I PKA is predominantly cytoplasmic, whereas type II PKA usually associates with specific cellular structures and organelles. The intracellular organization of PKA is controlled through the association with AKAPs (A-kinase-anchoring proteins) [, , ].PKA plays a role in the regulation of diverse processes such as growth, development, memory, metabolism, gene expression, immunity, and lipolysis. The cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis []. The cAMP/PKA pathway acts downstream of GPCRs and regulates the activities of key molecules involved in insulin secretion, including GLUT2, KATP, and Cav [].This entry includes cAMP-dependent protein kinase catalytic subunit alpha/beta (C-alpha/C-beta) from animals and their homologue, C-gamma, found in higher primates. C-gamma appears to have no function as a mature protein [].
This superfamily represents the GAF domain and domains sharing protein structural similarity, such as the C-terminal domain of the transcription regulator IclR, the C-terminal domain of the heat-inducible transcription repressor HrcA, and the phytochrome chromophore attachment domain.The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in guanylyl cyclases and phytochromes [, ]. The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain []. Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively; these products up-regulate catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding.Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region [].
This entry represents ATP-binding cassette sub-family C member 4 (MRP4 or ABCC4) from animals. It belongs to the MRP (multidrug resistance protein) subfamily of the ATP-binding cassette (ABC) transporter family []. MRP4 is a broad specificity organic anion exporter that seems to be able to mediate the transport of conjugated steroids, prostaglandins, and glutathione []. It can localise to both basolateral and apical membranes in polarised cells, depending on the tissue where it is found []. Together with CFTR, MRP4 functions in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes []. MRP4 has been implicated in the high proliferative growth of some tumors including prostate tumors and neuroblastoma [, ]. It confers resistance to anticancer agents including thiopurine analogs, MTX and topotecan []. The ABC transporter family is a group of membrane proteins that use the hydrolysis of ATP to power the translocation of a wide variety of substrates across cellular membranes. ABC transporters minimally consist of two conserved regions: a highly conserved nucleotide-binding domain (NBD) and a less conserved transmembrane domain (TMD). Eukaryotic ABC proteins are usually organised either as full transporters (containing two NBDs and two TMDs), or as half transporters (containing one NBD and one TMD), that have to form homo- or heterodimers in order to constitute a functional protein [].
This entry represents the dimerization/docking (D/D) domain of RIbeta, the Type I beta Regulatory subunit of cAMP-dependent protein kinase. RIbeta is expressed highly in the brain and is associated with hippocampal function. The R subunit contains an N-terminal dimerization/docking (D/D) domain, a linker with an inhibitory sequence, and two c-AMP binding domains. The D/D domain dimerizes to form a four-helix bundle that serves as a docking site for A-kinase-anchoring proteins (AKAPs), which facilitates the localization of PKA to specific sites in the cell [, ]. cAMP-dependent protein kinase (PKA) is a serine/threonine kinase (STK), catalysing the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The inactive PKA holoenzyme is a heterotetramer composed of two phosphorylated and active catalytic subunits with a dimer of regulatory (R) subunits. Activation is achieved through the binding of the important second messenger cAMP to the R subunits, which leads to the dissociation of PKA into the R dimer and two active subunits. There are two classes of R subunits, RI and RII; each exists as two isoforms (alpha and beta) from distinct genes. These functionally non-redundant R isoforms allow for specificity in PKA signalling. RI subunits are pseudo-substrates as they do not contain a phosphorylation site in their inhibitory site unlike RII subunits. PKA is present ubiquitously in cells and interacts with many different downstream targets. It plays a role in the regulation of diverse processes such as growth, development, memory, metabolism, gene expression, immunity, and lipolysis [, ].
Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family []. They participate in differentiation and growth of diverse cell types. Inhibin inhibitssecretion of follicle-stimulating hormone by the pituitary []. Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits. Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains. Follistatin is bound to inhibin and activin and indirectly modulates the FSH release. In turn, FSH stimulates inhibin gene expression in the ovarian follicle [], probably mediated by cAMP []. The serum levels of inhibin, activin, and follistatin are elevated in pregnant women and decrease after delivery []. Genes coding for mouse activin beta C and beta E are closely linked and exhibit a liver-specific expression pattern in adult tissues.
Calcitonin []is a 32 amino acid polypeptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in the blood, by promoting the incorporation of these ions in the bones. This is the alpha type. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. CGRP induces vasodilatation in a variety of vessels, including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.Islet amyloid polypeptide (IAPP) [](also known as diabetes-associated peptide (DAP), or amylin) is a peptide of 37 amino acids that selectively inhibits insulin-stimulated glucose utilisation and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Structurally, IAPP is closely related to CGRP.Calcitonin receptor-stimulating peptide 1 stimulates cAMP production via the calcitonin receptor.Two conserved cysteines in the N-terminal of these peptides are known to be involved in a disulphide bond. The C-terminal residue of all three peptides is amidated.xCxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxx-NH(2)| | Amide group+-----+'C': conserved cysteine involved in a disulphide bond.
Adenylate cyclase catalyses the conversion of ATP to 3',5'-cyclic AMP (cAMP) and pyrophosphate. It plays an essential role in the regulation of cellular metabolism by catalysing the synthesis of a second messenger, cAMP. G protein-mediated signalling is implicated in yeast and fungal cAMP pathways. The cAMP-PKA pathway consists of an extracellular ligand-sensitive G protein-coupled receptor, a G protein signal transmitter, and the effector adenylate cyclase. The product of adenylate cyclase, cAMP, acts as an intracellular second messenger [].GTP-bound RAS2 is required to elicit magnesium-dependent adenylyl cyclase activity in Saccharomyces cerevisiae. In Schizosaccharomyces pombe, however, the cyclase is probably not regulated by RAS proteins, but is activated by git1.In S. pombe, Gpa2 Galpha binds an N-terminal domain of adenylate cyclase, comprising a moderately conserved sequence, which is within a region that is poorly related to other fungal adenylate cyclases. Adenylate cyclase is directly activated by a fungal G protein, which suggests a distinct activation mechanism from that of mammals [].This fungal domain interacts with the alpha subunit of heterotrimeric G proteins [].
Calcitonin []is a 32 amino acid polypeptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in the blood, by promoting the incorporation of these ions in the bones. This is the alpha type. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. CGRP induces vasodilatation in a variety of vessels, including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.Islet amyloid polypeptide (IAPP) [](also known as diabetes-associated peptide (DAP), or amylin) is a peptide of 37 amino acids that selectively inhibits insulin-stimulated glucose utilisation and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Structurally, IAPP is closely related to CGRP.Calcitonin receptor-stimulating peptide 1 stimulates cAMP production via the calcitonin receptor.Two conserved cysteines in the N-terminal of these peptides are known to be involved in a disulphide bond. The C-terminal residue of all three peptides is amidated.xCxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxx-NH(2)| | Amide group+-----+'C': conserved cysteine involved in a disulphide bond.This entry represents procalcitonin (before cleavage into the calcitonin peptide) and adrenomedullin.
Structural domains comprising this superfamily share the structure of two shown to be homologous GTPase activating proteins for Rap and Ran. Both are Ras-like guanine-nucleotide-binding proteins (GNBPs) involved in a variety of signal-transduction processes and their activity is regulated by GEFs and GAPs.Rap small G proteins have been implicated in various cellular processes such as exocytosis, cAMP signalling, cell adhesion and cell proliferation. Rap proteins acts as molecular switches, with an active GTP-bound form and an inactive GDP-bound form []. The inactive GDP bound form is promoted by GTPase-activating proteins (GAPs). GAP proteins specific for Rap contain a conserved region of around 200 amino-acid residues, the RapGAP domain. This domain can accelerate the GTP hydrolysis activity of Rap by five orders of magnitude [].Ran, also known as GTP-binding nuclear protein, is on the other hand essential for the translocation of RNA and proteins through the nuclear pore complex and has been implicated in the control of DNA synthesis and cell cycle progression. Proteins known to contain a Rap-GAP domain include:RAP1 GTPase activating protein (RAP1GAP).Mammalian tuberin protein, the product of a familial tuberous sclerosis gene which, when deleted, causes begnin tumours. It also have a GAPactivity for Rab5 [].Drosophila Gigas protein, an homologue of tuberin involved in regulation of cell cycle.Mammalian tuberin-like protein TULIP.GTPase-activating protein Spa-1. It functions as a negative regulator for the activation of Rap1, thereby having a negative effect on cell adhesion[].
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, withcalculated molecular mass of~36kDa, and potential N-linked glycosylation and phosphorylation sites[]. The melanocortin 4 receptor (MC4-R) is regulated by opiateadministration []. Rat MC4-R is 95% identical to human MC4-R, and thepotency of melanocortin peptides to stimulate cAMP production is similar inthese two species homologues []. Expression of MC4-R mRNA was found to beenriched in the striatum, nucleus accumbens, and periaque-ductal gray, allof which are regions implicated in the behavioral effects of opiates(and are regions in which MC1-, MC3- and MC5-R are expressed at low orundetectable levels) []. MC4-R mRNA has been found in multiple sites invirtually every brain region, including the cortex, thalamus, hypothalamus,brainstem, and spinal cord []. Unlike the MC3-R, MC4-R mRNA is found inboth parvicellular and magnocellular neurons of the paraventricular nucleusof the hypothalamus, suggesting a role in the central control of pituitaryfunction [].
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 glucagon receptor (GR) plays a central role in regulating the level of blood glucose by controlling the rate ofhepatic glucose production and insulin secretion []. GR is expressed predominantly in liver, kidney, adrenal, lung and stomach, with lower levels of expression detected in brown and white adipose tissue, cerebellum, duodenum and heart []. Their role in the control of blood glucose concentrations makes glucagon and GR especially important to studies of diabetes, in which the loss of control over blood glucose concentrations clinically defines the disease []. GR is similar to the secretin-like receptor superfamily. It can transduce signals leading to the accumulation of two different second messengers - i.e., both cAMP and calcium [].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 [].
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 [].For the CRF-R2 receptor, at least 2 splice forms with different 5'-coding sequences (CRF2 alpha and CRF2 beta) have been identified in rat []. The sequence of the CRF-R is highly conserved between species, the majority of the sequence divergence occuring in the putative signal peptide and extracellular N-terminal domain. The relative abundance of CRF-R2 messenger RNA appears to be lower in humans than in rats for the heart and skeletal tissues studied to date []. CRF-R2 stimulates cAMP production in response to CRF and known CRF-like agonists []. CRF and the non-mammalian CRF-related peptides sauvagine and urotensin I stimulate adenylate cyclaseactivity in a dose-dependent manner, with a rank order of potency thatdiffers from that of the CRF1 receptor (sauvagine>urotensin>=rat/human CRF>ovine CRF). The differences in the pharmacological profiles and tissue distributions of CRF-R1 and CRF-R2 suggests important functionaldifferences between the two 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 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 glucagon receptor (GR) plays a central role in regulating the level ofblood glucose by controlling the rate of hepatic glucose production and insulin secretion []. GR is expressed predominantly in liver, kidney, adrenal, lung and stomach, with lower levels of expression detected inbrown and white adipose tissue, cerebellum, duodenum and heart []. Their role in the control of blood glucose concentrations makes glucagon and GR especially important to studies of diabetes, in which the loss of control over blood glucose concentrations clinically defines the disease []. GR is similar to the secretin-like receptor superfamily. It can transduce signals leading to the accumulation of two different second messengers - i.e., both cAMP and calcium [].
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 NT1 receptor was cloned in 1990 from rat brain and found to act as ahigh affinity, levocabastine insensitive receptor for neurotensin []. The affinity of neurotensin for the receptor could be decreased by both sodium ions and guanosine triphosphate (GTP) []. The NT1 receptor is expressed predominantly in the brain and intestine. In the brain, expression has been found in the diagonal band of Broca, medial septal nucleus, nucleus basalis magnocellularis, suprachiasmatic nucleus, supramammillary area, substantia nigra and ventral tegmental area. The receptor is also expressed in the dorsal root ganglion neurones of the spinal cord. The predominant response upon activation of the receptor by neurotensin is activation of phospholipase C, causing an increase in intracellular calcium levels. The receptor can also stimulate cAMP formation, MAP kinase activation and the induction of growth related genes, such as krox-24 [].
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 [, , ].This entry spans the seven transmembrane regions of rhodopsin-like GPCRs. It also identifies some non rhodopsin-like GPCRs, including a number of taste receptors and vomeronasal 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 [, , ].This entry represents the G protein-coupled receptor, rhodopsin-like 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 [].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.
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 [].
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 insect octopamine receptor mediates the attenuation of adenylate cyclaseactivity. Sequence and pharmacological comparisons indicate that theoctopamine receptor is unique, but closely related to mammalian adrenergicreceptors, perhaps as an evolutionary precursor [, ].
The adrenoceptors (or adrenergic receptors) are rhodopsin-like G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. The clinical uses of adrenergic compounds are vast. Agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. These drugs are also useful in several other therapeutic situations including shock, premature labour and opioid withdrawal, and as adjuncts to general anaesthetics.There are three classes of adrenoceptors, based on their sequence similarity, receptor pharmacology and signalling mechanisms []. These three classes are alpha 1 (a Gq coupled receptor), alpha 2 (a Gi coupled receptor) and beta (a Gs coupled receptor), and each can be further divided into subtypes []. The different subtypes can coexist in some tissues, but one subtype normally predominates.There are three subtpyes of alpha 2 adrenoceptors (2A-C). The receptors are usually found presynaptically, where they inhibit the release of noradrenaline, and thus serve as an important receptor in the negative feedback control of noradrenaline release [, , , ]. Postsynaptic alpha 2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of the receptors causes platelet aggregation [], blood vessel constriction [, ]and constriction of vascular smooth muscle []. Agonists of alpha 2 adrenergic receptors are frequently used in veterinary anaesthesia, where they affect sedation, muscle relaxation and analgesia through their effects on the CNS []. Alpha 2 adrenoceptors are coupled through the Gi/Go mechanism, inhibiting adenylate cyclase activity and downregulating cAMP formation. This entry represents alpha 2C receptor, it is found mainly in the brain and kidney, and is absent in spleen, aorta, heart, liver, lung, skeletal muscle [, ].
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 [, , ].This entry represents a predicted G protein coupled receptor 152 orphan, GPR152.
Melatonin is a naturally occurring compound found in animals, plants, and microbes [, ]. In animals melatonin is secreted by the pineal gland during darkness [, ]. It regulates a variety of neuroendocrine functions and is thought to play an essential role in circadian rhythms []. Drugs that modify the action of melatonin, and hence influence circadian cycles, are of clinical interest for example, in the treatment of jet-lag []. Many of the biological effects of melatonin are produced through the activation of melatonin receptors [], which are members of rhodopsin-like G protein-coupled receptor family. There are three melatonin receptor subtypes. Melatonin receptor type 1A and melatonin receptor type 1B are present in humans and other mammals []while melatonin receptor type 1C has been identified in amphibia and birds []. There is also a closely-related orphan receptor, termed melatonin-related receptor type 1X (also known as GPR50) [], is yet to achieve receptor status from the International Union of Basic and Clinical Pharmacology (IUPHAR), since a robust response mediated via the protein has not been reported in the literature. Melatonin receptor type 1C receptors are 80% identical and are distinct from 1A and 1B subtypes. Similar ligand binding and functional characteristics are observed in expressed 1A and 1C receptors. The melatonin receptors inhibit adenylyl cyclase via a pertussis-toxin-sensitive G-protein, probably of the Gi/Go class. This entry represents melatonin receptor 1C, which is found in birds, fish and amphibians, but not in humans []. It has been shown that the widespread distribution of 1C in brain provides a molecular substrate for the profound actions of melatonin in birds []. Also, in amphibians, very low concentrations of melatonin activate the 1C receptor subtype, triggering movement of granules toward the cell centre, thus lightening skin colour. 1C receptor activation reduces intracellular cAMP via a pertussis toxin-sensitive inhibitory G-protein (Gi) [].
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 ofconsiderable 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 delta opioid receptor has a more discrete distribution in the CNSrelative to the mu and kappa opioid receptors: it is found in the cerebralcortex, amygdala, nucleus accumbens, olfactory tubercle and pontinenucleus. It is also found in certain smooth muscles, e.g. hamster vasdeferens, and in cell lines. Delta-receptors mediate analgesia.
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 [, , ].Growth hormone secretagogue receptor (GHSR) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin []. Ghrelin also increases growth hormone (GH) release []. The motilin receptor, also known as GPR38, shares significant amino acid sequence identity with GHSR [].
