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 ��-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.
This domain is found at the C-terminal of Filamentation induced by cAMP protein Fic () from Oleidesulfovibrio alaskensis and similar bacterial sequences. This domain adopts a winged helix structure (). It is often found associated with . This domain is also found in some archaeal sequences.
This family includes Tiny macrocysts protein B (TmcB) and C (TmcC) from the social amoeba Dictyostelium discoideum, as well as related proteins from other eukaryotes. TmcB is a multi-pass membrane protein that acts as a regulator of the cAMP signalling pathway specific to sexual development. It controls the levels of external cAMP by regulating the expression of phosphodiesterase pdsA and its inhibitor pdiA []. TmcC is also a multi-pass membrane protein involved in sexual development, though its disruption does not affect the cAMP response []. Members of this family often contain PAS domains and tetratricopeptide (TPR) repeats.
This is a region of tetratricopeptide (TPR)-like repeats found in Tiny macrocysts protein B and C from Dictyostelium discoideum (TmcB and TmcC) and similar eukaryotic proteins. TmcB is a regulator of the cAMP signalling pathway specific to sexual development. It controls the levels of external cAMP by regulating the expression of phosphodiesterase PdsA and its inhibitor PdiA. Knockout mutants of tmcC gene were indistinguishable from the wild type cells with respect to the cAMP response, suggesting that this gene is relevant to other processes [].
This entry represents the second domain of adenylate cyclase activation protein git1 from Schizosaccharomyces species. Git1 is involved in the glucose/cAMP signalling pathway and is required for maintaining basal cAMP levels and for producing a glucose-triggered cAMP response []. The full-length protein interacts with adenylate cyclase (cyr1) and localises to the cytoplasm, nucleus, and spindle pole body. Git1 contains Munc13 homology domains which are characteristic of proteins involved in vesicle priming and membrane trafficking. This domain is all-helical.
This entry represents differentiation-associated protein 2 (DIA2), a protein with an essential role in the initiation of differentiation in Dictyostelium discoideum []. DIA2 is also required for cAMP signalling []. The protein is localised to the endoplasmic reticulum and vacuole, changing location from endoplasmic reticulum to pre-spore-specific vacuoles during late development []. DIA2 accumulates in differentiating cells starved just before the PS point, with no detectable expression in vegetatively growing cells [, ]. Members of this family are also involved in the transduction of cAMP signalling pathways.
This entry represents a domain found in differentiation-associated protein 2 (DIA2) from Dictyostelium discoideum, a protein with an essential role in the initiation of differentiation in Dictyostelium discoideum []. This entry also includes related proteins which are also involved in the transduction of cAMP signalling pathways.DIA2 is also required for cAMP signalling []. The protein is localised to the endoplasmic reticulum and vacuole, changing location from endoplasmic reticulum to pre-spore-specific vacuoles during late development []. DIA2 accumulates in differentiating cells starved just before the PS point, with no detectable expression in vegetatively growing cells [, ].
This entry represents the third domain of yeast adenylate cyclase activation protein git1 and similar fungal sequences. Git1 is involved in the glucose/cAMP signalling pathway and is required for maintaining basal cAMP levels and for producing a glucose-triggered cAMP response []. This protein interacts with adenylate cyclase (cyr1) and localises to the cytoplasm, nucleus, and spindle pole body. Git1 contains Munc13 homology domains which are characteristic of proteins involved in vesicle priming and membrane trafficking. This entry also includes the Exocytic regulator ync13 from S.pombe, which is involved in secondary septum formation during cytokinesis [, ]. The specific function of this TPR-like fold domain remains to be determined.
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 [, , ].
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.
This entry represents the N-terminal domain of class-I adenylate cyclases.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 second domain of class-I adenylate cyclases. It is composed of ��-helices.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 third domain of class-I adenylate cyclases. It is predicted to contain anti-parallel ��-sheets and ��-helices.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 fourth domain of class-I adenylate cyclases. It is predicted to contain anti-parallel ��-sheets and ��-helices.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 C-terminal domain of class-I adenylate cyclases. It is predicted to contain anti-parallel ��-sheets and an ��-helix.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 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 [].
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 the heterotrimeric G protein gamma subunit GPG1, found in budding yeasts (Saccharomycetaceae). GPG1 is a component of heterotrimeric G proteins, which function as modulators in transmembrane signalling systems []. GPG1 interacts with the beta subunits GPB1 and GPB2 []. The protein is involved in cAMP level regulation and controls pseudohyphal and haploid invasive growth []. GPG1 localises to the cytoplasm.
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 [].
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) .
This entry represents the first periplasmic binding protein-like domain []found in receptor-type adenylate cyclase GRESAG 4.1/3 and its homologues, mainly found in trypanosoma.Receptor-type adenylate cyclase GRESAG 4.1/3 are class II adenylate cyclases (ACs) () that occur as multiple isozymes in Trypanosoma brucei. GRESAG 4.1 likely acts as a receptor for an unknown ligand and is involved in cyclic AMP (cAMP) production. cAMP is a critical signalling molecule in T. brucei, playing a role in processes such as differentiation and adaptation to environmental changes. GRESAG 4.1 is expressed in both bloodstream and procyclic forms of the parasite, suggesting it has a role across multiple life stages. Its localisation on the flagellum indicates it may be involved in sensing extracellular signals and transmitting them via cAMP signalling pathways, which are essential for parasite survival and development [, ].
This family of proteins is involved in the cellular anchoring of protein kinase A (PKA) regulatory subunits. Members of this family interact with the type II regulatory subunits of PKA, a pivotal enzyme in the cAMP signaling pathway, and play a crucial role in localizing the kinase to specific subcellular compartments. Through this targeting mechanism, they help orchestrate the spatial and temporal dynamics of PKA signaling, which is essential for a multitude of cellular processes.
This entry represents the N-terminal domain in A-kinase anchor protein SPHKAP. SPHKAP is an anchoring protein that binds preferentially to the type I regulatory subunit of c-AMP-dependent protein kinase (PKA type I) and targets it to distinct subcellular compartments. It also may act as a converging factor linking cAMP and sphingosine signaling pathways. It plays a regulatory role in the modulation of SPHK1 [, ]. This domain is also found in the A-kinase anchor protein 11.
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.
Yeast adenylate cyclase (CYAA/CYR1) is required for cAMP production and cAMP-dependent protein kinase signalling. It is a scaffold protein for Ras2-Ira interaction []. This entry represents the C-terminal domain which contains a second Ras binding site (the first resides in the LRR region) which is involved in a GTP-independent weak interaction between Ras and a complex of adenylate cyclase and Srv2 protein []. These two Ras binding sites are required for normal Ras2 downregulation [].
The adenylyl cyclase class-3/4/guanylyl cyclase family is involved in the synthesis of second messengers, cAMP or cGMP, from ATP or GTP respectively. These enzymes play essential roles in regulating cellular metabolism and responses to external signals. Some family members act as photoreceptors or potential receptors for unknown ligands, indicating a sensory function. The family includes pH-sensitive and photoactivated subtypes, and their activity can be modulated by various factors such as light, adenosine, GTP, and membrane potential changes.
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 [].
cAMP-dependent kinase regulatory subunits play a crucial role in cAMP signaling within cells. They are involved in the regulation of protein kinases (PKA) activity by inhibiting the kinase in the absence of cAMP [, , ]. Upon binding of cAMP, these regulatory subunits undergo a conformational change that leads to the dissociation of the regulatory subunit dimer from the catalytic subunits, thus activating the kinase []. This family is involved in various cellular processes including the regulation of metabolic pathways, cell growth, and proliferation, as well as the rhythmic contraction of muscles and neuronal activity regulation in the brain [].This entry also contains cAMP/cGMP-dependent 3',5'-cAMP/cGMP phosphodiesterase B, thought to function as a cAMP-stimulated cAMP-phosphodiesterase which may play a role in regulating the cAMP relay response [, , ].Acetyltransferase Pat catalyses the acetylation of the epsilon-amino group of a highly conserved lysine residue in acetyl-CoA synthetase (ACS) and of the universal stress protein (USP) MSMEG_4207. Acetylation results in the inactivation of ACS activity and could be important for mycobacteria to adjust to environmental changes [, ].
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 of individual cells into a multicellular organism, and regulate the expression of a large number of developmentally-regulated genes [, , ]. The amino acid sequences of the receptors contain high proportions of hydrophobic residues grouped into 7 domains, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins. However, while a similar 3D framework has been proposed to account for this, there is no significant sequence similarity between these families: the cAMP receptors thus bear their 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 [].
This family of proteins exhibits phosphodiesterase activity, specifically hydrolyzing artificial chromogenic substrates such as bis-p-nitrophenyl phosphate and, to a lesser extent, thymidine 5'-monophosphate p-nitrophenyl ester and p-nitrophenylphosphorylcholine. They do not show catalytic activity towards cyclic nucleotides like cAMP or cGMP, nor do they act on nucleotides or typical phospholipase substrates like phosphatidylcholine. The natural substrate for these enzymes remains unidentified. They are characterized by their membership in the metallophosphoesterase superfamily and are competitively inhibited by phosphate ions, suggesting a regulatory mechanism sensitive to phosphate levels.
This family of proteins includes cyclic AMP (cAMP)-inducible proteins such as BP74 from Dictyostelium discoideum. These proteins are typically regulated by cAMP, a key signaling molecule in many biological processes. The cAMP-inducible proteins can be involved in various cellular functions, including but not limited to, gene regulation, metabolic pathways, and cellular response to external stimuli. The exact role of BP74 is not clearly defined, but it is likely to be associated with the cellular response to cAMP signaling during the organism's development and differentiation processes.
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 the Calcineurin-like domain center around the metal-chelating residues. The structure typically comprises two sandwiched ��-sheets flanked by ��-helical segments, with the binuclear metal center located at the interface between two symmetrical halves of the molecule. This domain arrangement allows PAPs to perform their characteristic phosphatase activity under acidic conditions [].
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.
This entry represents the gammaherpesvirus G-protein coupled receptor (GPCR) BILF1 and related virus GPCR. These receptors are constitutively active and signal through Gi type G-proteins. BILF1 is a lytic gene in Epstein-Barr virus (EBV) and inhibits cAMP response element-binding protein (CREB) activation via stimulation of endogenous G proteins. The alcelaphine herpesvirus 1 homologue (A5) was found to be non-essential for the induction of malignant catarrhal fever in rabbits. Members of this family are 7-transmembrane GPCRs containing conserved cysteines in the amino terminus and extracellular loops, amino-terminal glycosylation sites, and intracellular phosphorylation sites [].
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. U-scoloptoxin(21)-Sm1/2a are uncharacterised proteins related to DH31.
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 tothe 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 [].
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 [].
Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of T lymphocytes. However, TCR-mediated signals alone are insufficient for efficient 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 the majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T cells 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 apoptosis of activated T cells, suggesting its importance in regulating long-term T cell survival [, , , ].Ligands for CD28 and the structurally related CTLA-4 (CD152) are the molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on professional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligands results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic tail. The phosphorylated motif subsequently interacts with the Src homology 2 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 substitute for CD28 signals, and stimulates IL-2 production when introduced into mature CD28-deficient cells. Another molecule affected by CD28 stimulation is the proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for Rac 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 of PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has been reported to affect nearly every pathway important for lymphocyte activation, leading to inhibition of T cell proliferation. Specifically, increased intracellular cAMP has been implicated in the induction of T cell anergy, a non-responsive state that occurs after T cells are stimulated through TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune 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 integrates mitogenic MEK and P13K-dependent signals from both TCR and CD28 [].
This entry represents a family of cyclic nucleotide-degrading phosphodiesterases. These enzymes are involved in the hydrolysis of cyclic nucleotides, such as cAMP and cGMP, into their corresponding nucleoside monophosphates. Members of this family include uncharacterized proteins from various Mycobacterium species, such as Mycobacterium bovis (strain ATCC BAA-935 / AF2122/97), Mycobacterium tuberculosis (strains CDC 1551 / Oshkosh and ATCC 25618 / H37Rv), and Mycobacterium leprae (strain TN). These proteins share sequence similarity and are classified under the AtsA family. The precise biological roles of these proteins in Mycobacterium species remain to be fully elucidated.
The olfactory receptor family is comprised of G-protein coupled receptors with the primary function of detecting odorants. These receptors are activated by a diverse array of chemical compounds, including organosulfur odorants with thioether groups, and in some cases, their activity is enhanced by copper binding. One member of the family also acts as a receptor for the hormone Asprosin, influencing glucose release from hepatocytes and regulating appetite and fertility. The activity of these receptors is typically mediated by G proteins that activate adenylyl cyclase, leading to an increase in intracellular cAMP levels.
This entry represents the RING-like U-box domain found in E3 ubiquitin-protein ligase CHIP.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 [, ].
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-�� 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 family includes the cyclic AMP-responsive element-binding protein 3 (CREB3) and related proteins such as CREB3L3 and CREB3L4, as well as the Caenorhabditis elegans homologue let-607. These proteins are endoplasmic reticulum (ER)-bound sequence-specific transcription factors that belong to the basic-leucine zipper (bZIP) family. They are activated by regulated intramembrane proteolysis (RIP) in response to ER stress, releasing a transcriptionally active N-terminal fragment that translocates to the nucleus to activate unfolded protein response (UPR) target genes [, ]. They bind to the cAMP response element (CRE) and other regulatory elements to modulate genes involved in cell survival, lipid metabolism, and inflammatory responses [, , , ].
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 bythe 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 [].
This entry represents a leucine rich repeat. A leucine-rich repeat (LRR) is a protein structural motif that forms an ��/�� horseshoe fold [, ]. Leucine-rich repeats are frequently involved in the formation of protein protein interactions [, ].This repeat is found in Follicle-stimulating hormone receptors (Fshr), Thyrotropin receptors, Lutropin-choriogonadotropic hormone receptor and related proteins. Fshr are G protein-coupled receptors for follitropin, the follicle-stimulating hormone. Through cAMP production it activates the downstream PI3K-AKT and ERK1/ERK2 signaling pathways [, ].This repeat is found in a large number of BSPA-like surface antigens from Trichomonas vaginalis.
This family of proteins includes G-protein coupled receptors (GPCRs) that are predominantly categorized as orphan receptors, which means their endogenous ligands are unknown. Members of this family are characterized by a significant level of constitutive activity, which is the ability to activate intracellular signaling pathways in the absence of a ligand. The signaling is primarily mediated through the G(s)-alpha protein, stimulating adenylate cyclase to increase intracellular cAMP levels. One member is identified as a high-affinity receptor for lysophosphatidic acid (LPA), indicating a role in mediating cellular responses to this lipid mediator. The family members are implicated in various functions, including potential roles in brain function and cellular signaling.
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 [, ].
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 [, , ].
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 at the N terminus of PDE1 predominantly from vertebrates. This domain adopts an all ��-helical structure. It is found next to the catalytic 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 [].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 at the N-terminal of high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8 (PDE8), PDE8A, and PDE8B, which are mainly found in vertebrates. PDE8A hydrolyses the second messenger cAMP, a key regulator of many important physiological processes []. This domain is predicted to adopt a Rossmann fold similar to CheY-type chemotaxis response regulators. This domain is also called REC 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 entry represents the second periplasmic binding protein-like domain []found in receptor-type adenylate cyclase GRESAG 4.1/3 and its homologues, mainly found in trypanosoma. It is usually found N-terminal to the adenylyl cyclase class-3/4/guanylyl cyclase domain (A/G_cyclase) (). In Trypanosoma brucei, the A/G_cyclase domain was crystalized and was named the catalytic domain () [].Receptor-type adenylate cyclase GRESAG 4.1/3 are class II adenylate cyclases (ACs) () that occur as multiple isozymes in Trypanosoma brucei. GRESAG 4.1 likely acts as a receptor for an unknown ligand and is involved in cyclic AMP (cAMP) production. cAMP is a critical signalling molecule in T. brucei, playing a role in processes such as differentiation and adaptation to environmental changes. GRESAG 4.1 is expressed in both bloodstream and procyclic forms of the parasite, suggesting it has a role across multiple life stages. Its localisation on the flagellum indicates it may be involved in sensing extracellular signals and transmitting them via cAMP signalling pathways, which are essential for parasite survival and development [, ].
This entry represents global transcription factors found in fungi.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 []. Sge1 is a global transcriptional regulator of pathogenicity. It acts as an activator of parasitic growth. It is not essential for colonisation or penetration of the root surface but is required for expression of genes encoding effectors that are secreted during infection. It is involved in conidiogenesis but is not required for conidial fitness, overall (colony) morphology, vegetative growth or carbon source utilisation [].
This domain is found C-terminal in the homologues of human KCTD2, KCTD5 and KCTD17 proteins that are members of the KCTD family. Genetic alternations in KCTD family members have been associated with neurodevelopmental disorders, epilepsy, autism, schizophrenia, movement disorders, obesity, and several cancers []. KCTD2, KCTD5, and KCTD17 are closely related BTB/POZ-domain proteins that act as adaptors in ubiquitin ligase complexes and modulators of neuronal signaling, particularly dopaminergic and cAMP pathways. They are expressed broadly but have especially important functions in the brain, where they help control neuronal excitability, movement, and cellular growth []. They define a phylogenetic subgroup of KCTD with highly similar BTB and C-terminal domains []. This domain adopts a simple structure composed of three-stranded antiparallel ��-sheet and ��-helix which connects the first and second strand []. Using its C-terminal domain, KCTD5 forms a central pentameric scaffold that simultaneously engages five Gbeta/gamma substrates [].
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.
Testis-specific serine/threonine-protein kinases (TSSKs) are almost exclusively expressed post meiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis [, , ]. There are five mammalian TSSK proteins which show differences in their localisation and timing of expression [, , ]. This entry represents the catalytic domain of TSSK4, also called TSSK5, which is expressed in testis from haploid round spermatids to mature spermatozoa. It mediates its autophosphorylation at Thr-197 in the T-loop region which is essential to its kinase activity [, ]. It phosphorylates Cre-Responsive Element Binding protein (CREB), facilitating the binding of CREB to the specific cis cAMP responsive element (CRE), which is important in activating genes related to germ cell differentiation []. Mutations in the human TSSK4 gene is associated with infertile Chinese men with impaired spermatogenesis [].
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 [].
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 [, ].
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [, , , ]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [, ]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.This entry represents CAP proteins from various organisms.
The KCNH potassium channel family consists of voltage-gated potassium channels that play a critical role in regulating the electrical excitability of cells. Members of this entry are mainly found in animals. These channels are characterized by their pore-forming alpha subunits, which mediate various potassium currents. The S4 segment, often serving as the voltage-sensor, contains positively charged amino acids crucial for function. Members of the family are involved in modulating channel properties through mechanisms such as cAMP and subunit assembly. Some are involved in specific physiological processes like heart rate regulation (IKr current) and cell proliferation and differentiation. The activity of these channels can be influenced by factors such as calmodulin binding and intracellular phosphatidylinositol phosphates [, , ].
The Cyclic Nucleotide-Gated Cation Channel family is involved in various signal transduction pathways, primarily in sensory neurons. Members of the family are activated by cyclic nucleotides (cAMP or cGMP), leading to the opening of nonselective cation channels. In visual systems, they play a crucial role in phototransduction by mediating the depolarization of photoreceptors in response to changes in cGMP levels due to light exposure. In olfactory systems, they are essential for odorant signal transduction, where cAMP serves as a second messenger. The channels are also involved in adaptation processes, allowing rapid response to stimuli and extending the range of detection. Some family members are implicated in other cellular functions, such as sperm chemotaxis and maintaining normal axon morphology.
The cyclic nucleotide phosphodiesterase class-III family encompasses enzymes that hydrolyze cyclic nucleotides to their corresponding monophosphates, thus playing a crucial role in regulating intracellular concentrations of cyclic AMP (cAMP) and cyclic GMP (cGMP). These enzymes modulate cAMP-dependent pathways, influencing responses to nutritional stress and virulence factor regulation in various organisms. Some family members exhibit dual specificity for cAMP and cGMP, while others preferentially hydrolyze glycerophosphodiesters, indicating a broader substrate specificity. The activity of these phosphodiesterases is regulated by divalent metal ions such as Ca(2+), Mg(2+), and Mn(2+), with some also being influenced by the presence of transition-metal ions or activated by iron. The family includes enzymes with a C-terminal extension that adjusts substrate alignment in the active site and affects subcellular localization and expression levels.
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.
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.
This entry represents the POPDC family of proteins, also known as the Popeye (POP) family, which includes POPDC1, 2 and 3 and is mainly restricted to vertebrates. It is preferentially expressed in developing and adult striated muscle []. These proteins act as cAMP effectors [, , ]and play a role in cardiac pacemaking and conduction. The POPDC proteins have been shown to regulate potassium []and sodium channels [].POPDC1 has been associated with phenotypes including limb-girdle muscular dystrophy-25 (), cardiac arrhythmias []and changes in POPDC protein expression have been linked to many cancers [].POPDC3 may play a role in the maintenance of heart function mediated, at least in part, through cAMP-binding and it is also important for skeletal muscle function. It may play a role in the regulation of KCNK2/TREK-1-mediated current amplitude. Pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy [].
The HCN channel family comprises hyperpolarization-activated ion channels that are weakly selective for potassium over sodium ions. These channels are integral for generating pacemaker currents in the heart and neurons, influencing the rhythm of the heartbeat and neuronal excitability. They are also implicated in sensory processes, such as responses to sour stimuli. HCN channels are regulated by cyclic nucleotides; cAMP and cGMP can activate the channels, leading to tetramer assembly and channel opening. The S4 segment likely serves as a voltage-sensor, with a pattern of positively charged amino acids. Activity can also be modulated by intracellular factors like chloride ions and pH levels. Some family members are sensitive to inhibition by compounds such as Cs(1+), ZD7288, and ivabradine.
The Hydroxycarboxylic Acid Receptor family includes G-protein coupled receptors that mediate various physiological responses to hydroxycarboxylic acids, eicosanoids, and other ligands. Members of this family act as receptors for compounds such as L-lactate, nicotinic acid, (D)-beta-hydroxybutyrate, and 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-S-HETE). They are involved in processes such as anti-lipolysis, cell growth, inflammation, cancer promotion, and immune responses. Activation of these receptors can lead to signaling pathways involving inhibition of adenylyl cyclase, reduced cAMP levels, and activation of ERK1/2, MEK, and NF-kappa-B. Some receptors also play roles in apoptosis of mature neutrophils and in the regulation of adipocyte lipolysis. The family is characterized by its structural similarity to the G-protein coupled receptor 1 family and its ability to bind specific ligands with high affinity, mediating diverse biological effects.
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.
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.
This entry represents the seven transmembrane segments of G-protein coupled receptor 174 (GPR174).GPR174 has been identified as a lysophosphatidylserine receptor that enhances intracellular cAMP formation [, ]. It is involved in the immune response and has been linked to autoimmune diseases [, ]. GPR174 is a member of the class A family of GPCRs, which represents a widespread protein family that includes the light-sensitive rhodopsin as well as receptors for biogenic amines, lipids, nucleotides, odorants, peptide hormones, and a variety of other ligands []. A general feature of GPCR signalling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes [, , , , , ].
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 family of prokaryotic proteins includes enzymes involved in nucleotide metabolism. Some members of this family are capable of degrading RNA oligonucleotides, particularly those with a length of five nucleotides, by cleaving them from the 3' to 5' direction. They exhibit a preference for adenine-rich RNA sequences and show reduced activity on shorter oligonucleotides or those with a length of 24 nucleotides []. Additionally, some family members possess the ability to hydrolyse cyclic nucleotides such as cAMP and cGMP into their corresponding 5'-monophosphates, without exhibiting phosphohydrolase activity towards phospholipids or phosphorylated sugars []. The enzymatic activities of these proteins are crucial for the regulation of intracellular nucleotide levels and the maintenance of RNA turnover.
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 immunity and 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 ��-helical structureconsisting of 16 ��-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 the catalytic domain of approximately 270 amino acids at the carboxyl terminus in PDEase enzymes. 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 ��-helical structure consisting of 16 ��-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 [, , ].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.
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 [, ].
The V2 receptor is found in high levels in the osmoregulatory epithelia of the terminal urinary tract, where it stimulates water reabsorption. It is also present in lower levels in the endothelium and blood vessels of some species, where it induces vasodilation. In the CNS, binding sites are found in the subiculum, with lower levels in caudate-putamen and islands of Calleja. The receptor is involved in an effector pathway that forms cAMP through activation of G proteins.Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present at high levels in the posterior pituitary. Vasopressin has an essential role in the control of the water content of the body, acting in the kidney to increase water and sodium absorption. In higher concentrations, vasopressin stimulates contraction of vascular smooth muscle, stimulates glycogen breakdown in the liver, induces platelet activation, and evokes release of corticotrophin from the anterior pituitary. Vasopressin and its analogues are used clinically to treat diabetes insipidus.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 [, , ].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 [].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].In addition to their role in energy metabolism, purines (especially adenosine and adenine nucleotides) produce a wide range of pharmacological effects mediated by activation of cell surface receptors. Distinct receptors exist for adenosine. In the periphery, the main effects of adenosine include vasodilation, bronchoconstriction, immunosuppresion, inhibition of platelet aggregation, cardiac depression, stimulation of nociceptive afferents, inhibition of neurotransmitter release and inhibition of the release of other factors, e.g. hormones. In the CNS, adenosine exerts a pre- and post-synaptic depressant action, reducing motor activity, depressing respiration, inducing sleep and relieving anxiety. The physiological role of adenosine is thought to be to adjust energy demands in line with oxygen supply. Many of the clinical actions of methylxanthines are thought to be mediated through antagonism of adenosine receptors. Four subtypes of receptor have been identified, designated A1, A2A, A2B and A3.A2B receptors are widespread in the human brain relative to A2A receptors. By contrast, however, in the rat its mRNA is found only in low levels in the brain and it has a unique distribution in the periphery, high levels occurring in the intestine and bladder. The receptor stimulates cAMP through G proteins.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [, , ].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 four receptor 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 vertebrate corticotropin-releasing factor (CRF) receptors are predominantly expressed in central nervous system with high levels in cortex tissue, brain stem, and pituitary. They have two isoforms as a result of alternative splicing of the same receptor gene: CRF-R1 and CRF-R2, which differ in tissue distribution and ligand binding affinities. Recently, a third CRF receptor (CRF-R3) has been identified in catfish pituitary. The catfish CRF-R1 is highly homologous to CRF-R3. CRF is a 41-amino acid neuropeptide that plays a central role in coordinating neuroendocrine, behavioral, and autonomic responses to stress by acting as the primary neuroregulator of the hypothalamic-pituitary-adrenal axis, which controls the levels of cortisol and other stress related hormones. In addition, the CRF family of neuropeptides also includes structurally related peptides such as mammalian urocortin, fish urotensin I, and frog sauvagine. The actions of CRF and CRF-related peptides are mediated through specific binding to CRF-R1 and CRF-R2. CRF and urocortin 1 bind and activate mammalian CRF-R1 with similar high affinities. By contrast, urocortin 2 and urocortin 3 do not bind to CRF-R1 or stimulate CRF-R1-mediated cAMP formation. Urocortin 1 also shows high affinity for mammalian CRF-R2, whereas CRF has significantly lower affinity for this receptor. These evidence suggest that urocortin 1 is an endogenous ligand for CRF-R1 and CRF-R2.The CRF receptors are members of the B1 subfamily of class B GPCRs, also referred to as secretin-like receptor family, which includes receptors for polypeptide hormones of 27-141 amino-acid residues such as secretin, glucagon, glucagon-like peptide (GLP), calcitonin gene-related peptide, and parathyroid hormone (PTH) [, , ]. These receptors contain the large N-terminal extracellular domain (ECD), which plays a critical role in hormone recognition by binding to the C-terminal portion of the peptide. On the other hand, the N-terminal segment of the hormone induces receptor activation by interacting with the receptor transmembrane domains and connecting extracellular loops, triggering intracellular signalling pathways. All members of the B1 subfamily preferentially couple to G proteins of G(s) family, which positively stimulate adenylate cyclase, leading to increased intracellular cAMP formation and calcium influx. However, depending on its cellular location and function, CRF receptors can activate multiple G proteins, which can in turn stimulate different second messenger pathways [, , ].
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 ��-helices and a distinctive eight-stranded, antiparallel ��-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 ��-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 ��-helices and a distinctive eight-stranded, antiparallel ��-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 ��-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.
This entry includes insulin-like 3 from mammals, insulin-like peptide 4 (Ilp4 or dILP4) from fruit flies []and Gonad-stimulating substance (GSS) from Starfish.Insulin-like 3 (INSL3) is a secreted protein produced by testicular Leydig cells and in lower amounts by ovarian follicular theca interna cells and the corpus luteum []. It acts as a theca cell-derived growth factor for preantral follicle and its action is mediated by growth differentiation factor 9 []. Signaling through INSL3 and its cognate G protein-coupled receptor RXFP2 is important for testicular descent. It seems to be dispensable for spermatogenesis and fertility in adult males [].The function of Ilp4 is not clear.Gonad-stimulating substance (GSS) induces oocyte maturation and ovulation in vitro in ovarian fragments and triggers spawning behaviour and gamete release in vivo []. GSS probably mediates these effects through binding to a G protein-coupled receptor located in follicle cell membranes [, , ]. Upon receptor binding, GSS stimulates GTP-dependent adenylyl cyclase activity in follicle cell membranes of fully grown stage V ovaries, but not in younger stage IV ovaries, resulting in cAMP production [, ]. This in turn stimulates production of the maturation-inducing hormone 1-methyladenine specifically in stage V ovaries [, , ]. The absence of activity in stage IV ovaries is likely attributable to very low expression levels of the G protein alpha s subunit, which is not highly expressed in follicle cells until stage V [].
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 [].
This entry represents human G-protein coupled receptors 26 and 78 (GPR26778) and similar proteins from vertebrates. These proteins are constitutively active and coupled to increased cAMP formation. They are closely related based on sequence homology and comprise a conserved subgroup within the class A G-protein coupled receptor (GPCR) superfamily. Both receptors are widely expressed in selected tissues of the brain but their endogenous ligands are unknown []. GPR26 knockout mice showed increased levels of anxiety- and depression-like behaviours, whereas GPR78 has been implicated in susceptibility to bipolar affective disorder and schizophrenia [, , , , ].All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) ��-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signalling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes [, , , , , , ].
The 5-hydroxytryptamine receptor 4 (5-HT4R) is a member of the serotonin receptor family that belongs to the class A G protein-coupled receptor binds the neurotransmitter serotonin (5HT; 5-hydroxytryptamine) in the mammalian central nervous system (CNS) []. 5-HT4 receptors are selectively linked to G proteins of the G(s) family, which positively stimulate adenylate cyclase, causing cAMP formation and activation of protein kinase A [, , , , ]. 5-HT4 receptor-specific agonists have been shown to enhance learning and memory in animal studies. Moreover, hippocampal 5-HT4 receptor expression has been reported to be inversely correlated with memory performance in humans. All GPCRs have a common structural architecture comprising seven-transmembrane (TM) ��-helices interconnected by three extracellular and three intracellular loops []. A general feature of GPCR signalling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits []. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes [].
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 ��-helices and a distinctive eight-stranded, antiparallel ��-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 ��-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.
Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain [, ]. The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity [, , ]. In signaling, all can act via the Gi/o class [], whilst GAL2 also has Gq/11 as a major signaling route [].This entry represents the galanin receptor 1 subtype, which is expressed at significant levels in regions of the brain and spinal cord including the hypothalamus, amygdala, hippocampus, thalamus and brainstem. It has also been detected throughout the length of the human gastro-intestinal tract [, , , ]. Galanin receptor 1 reduces the concentration of cAMP [], opens G protein-coupled, inwardly rectifying K+ channels [], and stimulates MAP kinase activity []in a manner that is sensitive to pertussis toxin.
