seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736   1 MILVSTTSGIAACQVLIFREIHASLVPGPSERAGRRRRGHRTGS-PSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLV 79
Cdd:cd15388  170 VVFVLPTLIITVCQVLIFKEIHINIYLKSQIIVAVVKKKQLLSSrASSVAEVSKAMIKTVKMTLVIVLVYVLCWAPFFLV 249

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 443906736  80 QLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15388  250 QLWSVWDPKAPTEGATFTILMLLASLNSCTNPWIYM 285

vasopressin receptor 2, member of the class A family of seven-transmembrane G protein-coupled receptors; The vasopressin type 2 receptor (V2R) is a G(s)-coupled receptor that controls balance of water and sodium ion by regulating their reabsorption in the renal collecting duct. Mutations of V2R is responsible for nephrogenic diabetes insipidus. Vasopressin (also known as arginine vasopressin or anti-diuretic hormone) is synthesized in the hypothalamus and is released from the posterior pituitary gland. The actions of vasopressin are mediated by the interaction of this hormone with three receptor subtypes: V1aR, V1bR, and V2R. These subtypes are differ in localization, function, and signaling pathways. Activation of V1aR and V1bR stimulate phospholipase C, while activation of V2R stimulates adenylate cyclase. Although vasopressin and oxytocin differ only by two amino acids and stimulate the same cAMP/PKA pathway, they have divergent physiological functions. Vasopressin is involved in regulating blood pressure and the balance of water and sodium ions, whereas oxytocin plays an important role in the uterus during childbirth and in lactation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736   1 MILVSTTSGIAACQVLIFREIHASLVPGPSERAGRRRRGHRTGS-PSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLV 79
Cdd:cd15388  170 VVFVLPTLIITVCQVLIFKEIHINIYLKSQIIVAVVKKKQLLSSrASSVAEVSKAMIKTVKMTLVIVLVYVLCWAPFFLV 249

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 443906736  80 QLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15388  250 QLWSVWDPKAPTEGATFTILMLLASLNSCTNPWIYM 285

vasopressin receptor 2, member of the class A family of seven-transmembrane G protein-coupled receptors; The vasopressin type 2 receptor (V2R) is a G(s)-coupled receptor that controls balance of water and sodium ion by regulating their reabsorption in the renal collecting duct. Mutations of V2R is responsible for nephrogenic diabetes insipidus. Vasopressin (also known as arginine vasopressin or anti-diuretic hormone) is synthesized in the hypothalamus and is released from the posterior pituitary gland. The actions of vasopressin are mediated by the interaction of this hormone with three receptor subtypes: V1aR, V1bR, and V2R. These subtypes are differ in localization, function, and signaling pathways. Activation of V1aR and V1bR stimulate phospholipase C, while activation of V2R stimulates adenylate cyclase. Although vasopressin and oxytocin differ only by two amino acids and stimulate the same cAMP/PKA pathway, they have divergent physiological functions. Vasopressin is involved in regulating blood pressure and the balance of water and sodium ions, whereas oxytocin plays an important role in the uterus during childbirth and in lactation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736   1 MILVSTTSGIAACQVLIFREIHASLVPGPSERAGRRRRGHRTGS-PSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLV 79
Cdd:cd15388  170 VVFVLPTLIITVCQVLIFKEIHINIYLKSQIIVAVVKKKQLLSSrASSVAEVSKAMIKTVKMTLVIVLVYVLCWAPFFLV 249

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 443906736  80 QLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15388  250 QLWSVWDPKAPTEGATFTILMLLASLNSCTNPWIYM 285

oxytocin receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Oxytocin is a peptide of nine amino acids synthesized in the hypothalamus and is released from the posterior pituitary gland. Oxytocin plays an important role in sexual reproduction of both sexes and is structurally very similar to vasopressin. Although vasopressin and oxytocin differ only by two amino acids and stimulate the same cAMP/PKA pathway, they have divergent physiological functions. Vasopressin is involved in regulating blood pressure and the balance of water and sodium ions, whereas oxytocin plays an important role in the uterus during childbirth and in lactation.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 443906736  51 VSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15387  223 ISKAKIRTVKMTFVIVLAYIVCWTPFFFVQMWSVWDPNAPKEASPFIIAMLLASLNSCCNPWIY 286

vasopressin receptor subtype 1B, member of the class A family of seven-transmembrane G protein-coupled receptors; The V1b receptor is specifically expressed in corticotropes of the anterior pituitary and plays a critical role in regulating the activity of hypothalamic-pituitary-adrenal axis, a key part of the neuroendocrine system that controls reactions to stress, by maintaining adrenocorticotropic hormone (ACTH) and corticosterone levels. Vasopressin (also known as arginine vasopressin or anti-diuretic hormone) is synthesized in the hypothalamus and is released from the posterior pituitary gland. The actions of vasopressin are mediated by the interaction of this hormone with three receptor subtypes: V1aR, V1bR, and V2R. These subtypes are differ in localization, function, and signaling pathways. Activation of V1aR and V1bR stimulate phospholipase C, while activation of V2R stimulates adenylate cyclase. Although vasopressin and oxytocin differ only by two amino acids and stimulate the same cAMP/PKA pathway, they have divergent physiological functions. Vasopressin is involved in regulating blood pressure and the balance of water and sodium ions, whereas oxytocin plays an important role in the uterus during childbirth and in lactation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREIHASLVPGPSERAGRRRRGHRTGSPSEGAHV---SAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWD 86
Cdd:cd15386  181 LIVCYSLICYEICKNLKGKTQTSRSEGGGWRTQGMPSRVSSVrtiSRAKIRTVKMTFVIVLAYIACWAPFFSVQMWSVWD 260

                         90       100       110
                 ....*....|....*....|....*....|.
gi 443906736  87 PEAPLERPP---FVLLMLLASLNSCTNPWIY 114
Cdd:cd15386  261 ENAPDEDSSdfaFTITMLLASLSSCCNPWIY 291

adipokinetic hormone receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Adipokinetic hormone (AKH) is a lipid-mobilizing hormone that is involved in control of insect metabolism. Generally, AKH behaves as a typical stress hormone by mobilizing lipids, carbohydrates and/or certain amino acids such as proline. Thus, it utilizes the body's energy reserves to fight the immediate stress problems and subdue processes that are less important. Although AKH is known to responsible for regulating the energy metabolism during insect flight, it is also found in insects that have lost its functional wings and predominantly walk for their locomotion. AKH is structurally related to the mammalian gonadotropin-releasing hormone (GnRH) and they share a common ancestor. Both GnRH and AKH receptors are members of the class A of the seven-transmembrane, G-protein coupled receptor (GPCR) superfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREI-HASLVPGPSERAGRRRRGHrtgSPSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPE 88
Cdd:cd15382  183 IVFCYSLILCEIsRKSKEKKEDVSEKSSSVRL---RRSSVGLLERARSRTLKMTIVIVLVFIICWTPYFIMSLWYWFDRE 259

                         90       100
                 ....*....|....*....|....*...
gi 443906736  89 APLERPPFV--LLMLLASLNSCTNPWIY 114
Cdd:cd15382  260 SASKVDPRIqkGLFLFAVSNSCMNPIVY 287

rhodopsin receptor-like class A family of the seven-transmembrane G protein-coupled receptor superfamily; Class A rhodopsin-like receptors constitute about 90% of all GPCRs. The class A GPCRs include the light-sensitive rhodopsin as well as receptors for biogenic amines, lipids, nucleotides, odorants, peptide hormones, and a variety of other ligands. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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. Based on sequence similarity, GPCRs can be divided into six major classes: class A (rhodopsin-like family), class B (Methuselah-like, adhesion and secretin-like receptor family), class C (metabotropic glutamate receptor family), class D (fungal mating pheromone receptors), class E (cAMP receptor family), and class F (frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREIHASLVPGPSERagrrrrghrtgSPSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPE- 88
Cdd:cd00637  177 IIVCYVRIFRKLRRHRRRIRSSS-----------SNSSRRRRRRRERKVTKTLLIVVVVFLLCWLPYFILLLLDVFGPDp 245

                         90       100
                 ....*....|....*....|....*..
gi 443906736  89 APLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd00637  246 SPLPRILYFLALLLAYLNSAINPIIYA 272

vertebrate gonadotropin-releasing hormone receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; GnRHR, also known as luteinizing hormone releasing hormone receptor (LHRHR), plays an central role in vertebrate reproductive function; its activation by binding to GnRH leads to the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. GnRHR is expressed predominantly in the gonadotrope membrane of the anterior pituitary as well as found in numerous extrapituitary tissues including lymphocytes, breast, ovary, prostate, and cancer cell lines. There are at least two types of GnRH receptors, GnRHR1 and GnRHR2, which couple primarily to G proteins of the Gq/11 family. GnRHR is closely related to the adipokinetic hormone receptor (AKH), which binds to a lipid-mobilizing hormone that is involved in control of insect metabolism. They share a common ancestor and are members of the class A of the seven-transmembrane, G-protein coupled receptor (GPCR) superfamily.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 443906736  46 SEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLER-PPFV--LLMLLASLNSCTNPWIY 114
Cdd:cd15383  213 SSSDNIPKARMRTLKMTIVIVSSFIVCWTPYYLLGLWYWFSPEMLEQTvPESLshILFLFGLLNACLDPLIY 284

cholecystokinin receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group represents four G-protein coupled receptors that are members of the RFamide receptor family, including cholecystokinin receptors (CCK-AR and CCK-BR), orexin receptors (OXR), neuropeptide FF receptors (NPFFR), and pyroglutamylated RFamide peptide receptor (QRFPR). These RFamide receptors are activated by their endogenous peptide ligands that share a common C-terminal arginine (R) and an amidated phenylanine (F) motif. CCK-AR (type A, alimentary; also known as CCK1R) is found abundantly on pancreatic acinar cells and binds only sulfated CCK-peptides with very high affinity, whereas CCK-BR (type B, brain; also known as CCK2R), the predominant form in the brain and stomach, binds CCK or gastrin and discriminates poorly between sulfated and non-sulfated peptides. CCK is implicated in regulation of digestion, appetite control, and body weight, and is involved in neurogenesis via CCK-AR. There is some evidence to support that CCK and gastrin, via their receptors, are involved in promoting cancer development and progression, acting as growth and invasion factors. Orexins (OXs; also referred to as hypocretins) are neuropeptide hormones that regulate the sleep-wake cycle and potently influence homeostatic systems regulating appetite and feeding behavior or modulating emotional responses such as anxiety or panic. OXs are synthesized as prepro-orexin (PPO) in the hypothalamus and then proteolytically cleaved into two forms of isoforms: orexin-A (OX-A) and orexin-B (OX-B). OXA is a 33 amino-acid peptide with N-terminal pyroglutamyl residue and two intramolecular disulfide bonds, whereas OXB is a 28 amino-acid linear peptide with no disulfide bonds. OX-A binds orexin receptor 1 (OX1R) with high-affinity, but also binds with somewhat low-affinity to OX2R, and signals primarily to Gq coupling, whereas OX-B shows a strong preference for the orexin receptor 2 (OX2R) and signals through Gq or Gi/o coupling. The 26RFa, also known as QRFP (Pyroglutamylated RFamide peptide), is a 26-amino acid residue peptide that exerts similar orexigenic activity including the regulation of feeding behavior in mammals. It is the ligand for G-protein coupled receptor 103 (GPR103), which is predominantly expressed in paraventricular (PVN) and ventromedial (VMH) nuclei of the hypothalamus. GPR103 shares significant protein sequence homology with orexin receptors (OX1R and OX2R), which have recently shown to produce a neuroprotective effect in Alzheimer's disease by forming a functional heterodimer with GPR103. Neuropeptide FF (NPFF) is a mammalian octapeptide that has been implicated in a wide range of physiological functions in the brain including pain sensitivity, insulin release, food intake, memory, blood pressure, and opioid-induced tolerance and hyperalgesia. The effects of NPFF are mediated through neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R) which are predominantly expressed in the brain. NPFF induces pro-nociceptive effects, mainly through the NPFF1-R, and anti-nociceptive effects, mainly through the NPFF2-R.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFV-----LLMLLASLNSCTNPWIYA 115
Cdd:cd14993  223 KVARMLIVVVVLFALSWLPYYVLSILLDFGPLSSEESDENFllilpFAQLLGYSNSAINPIIYC 286

cholecystokinin receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Cholecystokinin receptors (CCK-AR and CCK-BR) are a group of G-protein coupled receptors which bind the peptide hormones cholecystokinin (CCK) or gastrin. CCK, which facilitates digestion in the small intestine, and gastrin, a major regulator of gastric acid secretion, are highly similar peptides. Like gastrin, CCK is a naturally-occurring linear peptide that is synthesized as a preprohormone, then proteolytically cleaved to form a family of peptides with the common C-terminal sequence (Gly-Trp-Met-Asp-Phe-NH2), which is required for full biological activity. CCK-AR (type A, alimentary; also known as CCK1R) is found abundantly on pancreatic acinar cells and binds only sulfated CCK-peptides with very high affinity, whereas CCK-BR (type B, brain; also known as CCK2R), the predominant form in the brain and stomach, binds CCK or gastrin and discriminates poorly between sulfated and non-sulfated peptides. CCK is implicated in regulation of digestion, appetite control, and body weight, and is involved in neurogenesis via CCK-AR. There is some evidence to support that CCK and gastrin, via their receptors, are involved in promoting cancer development and progression, acting as growth and invasion factors.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 443906736  53 AAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLER---PPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15206  194 EAKKRVIRMLFVIVVEFFICWTPLYVINTWKAFDPPSAARYvssTTISLIQLLAYISSCVNPITY 258

galanin receptor and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes G-protein coupled galanin receptors, kisspeptin receptor and allatostatin-A receptor (AstA-R) in insects. These receptors, which are members of the class A of seven transmembrane GPCRs, share a high degree of sequence homology among themselves. The galanin receptors bind galanin, a neuropeptide that is widely expressed in the brain, peripheral tissues, and endocrine glands. Galanin is implicated in numerous neurological and psychiatric diseases including Alzheimer's disease, eating disorders, and epilepsy, among many others. KiSS1-derived peptide receptor (also known as GPR54 or kisspeptin receptor) binds the peptide hormone kisspeptin (metastin), which encoded by the metastasis suppressor gene (KISS1) expressed in various endocrine and reproductive tissues. AstA-R is a G-protein coupled receptor that binds allatostatin A. Three distinct types of allatostatin have been identified in the insects and crustaceans: AstA, AstB, and AstC. They both inhibit the biosynthesis of juvenile hormone and exert an inhibitory influence on food intake. Therefore, allatostatins are considered as potential targets for insect control.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREIHASLVPGPSeragrrrrghrtgspSEGAhvSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEa 89
Cdd:cd14971  181 ICVCYAAMLRHLWRVAVRPVL---------------SEGS--RRAKRKVTRLVLVVVVLFAACWGPIHAILLLVALGPF- 242

                         90       100
                 ....*....|....*....|....*....
gi 443906736  90 PLERPPFVLLML---LASLNSCTNPWIYA 115
Cdd:cd14971  243 PLTYATYALRIWahcLAYSNSAVNPVLYA 271

invertebrate gonadotropin-releasing hormone receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; GnRHR, also known as luteinizing hormone releasing hormone receptor (LHRHR), plays an central role in vertebrate reproductive function; its activation by binding to GnRH leads to the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. GnRHR is expressed predominantly in the gonadotrope membrane of the anterior pituitary as well as found in numerous extrapituitary tissues including lymphocytes, breast, ovary, prostate, and cancer cell lines. There are at least two types of GnRH receptors, GnRHR1 and GnRHR2, which couple primarily to G proteins of the Gq/11 family. GnRHR is closely related to the adipokinetic hormone receptor (AKH), which binds to a lipid-mobilizing hormone that is involved in control of insect metabolism. They share a common ancestor and are members of the class A of the seven-transmembrane, G-protein coupled receptor (GPCR) superfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREIHASlvpgpSERAGRRRRGHRTGSPSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEA 89
Cdd:cd15384  182 MVTCYVLIFITLSKS-----SRDFQGLEIYTRNRGPNRQRLFHKAKVKSLRMSAVIVTAFILCWTPYYVIMIWFLFFNPY 256

                         90       100
                 ....*....|....*....|....*
gi 443906736  90 PLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15384  257 PLNDILFDVIFFFGMSNSCVNPLIY 281

somatostatin receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs) are composed of five distinct subtypes (SSTR1-5) that display strong sequence similarity with opioid receptors. All five receptor subtypes bind the natural somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. They share common signaling cascades such as inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase activity, and G-protein-dependent regulation of MAPKs.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQL--WAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15093  210 KVTRMVVMVVVVFVICWLPFYVLQLvnVFVQLPETPALVGVYHFVVILSYANSCANPILYG 270

cholecystokinin receptor type B, member of the class A family of seven-transmembrane G protein-coupled receptors; Cholecystokinin receptors (CCK-AR and CCK-BR) are a group of G-protein coupled receptors which bind the peptide hormones cholecystokinin (CCK) or gastrin. CCK, which facilitates digestion in the small intestine, and gastrin, a major regulator of gastric acid secretion, are highly similar peptides. Like gastrin, CCK is a naturally-occurring linear peptide that is synthesized as a preprohormone, then proteolytically cleaved to form a family of peptides with the common C-terminal sequence (Gly-Trp-Met-Asp-Phe-NH2), which is required for full biological activity. CCK-AR (type A, alimentary; also known as CCK1R) is found abundantly on pancreatic acinar cells and binds only sulfated CCK-peptides with very high affinity, whereas CCK-BR (type B, brain; also known as CCK2R), the predominant form in the brain and stomach, binds CCK or gastrin and discriminates poorly between sulfated and non-sulfated peptides. CCK is implicated in regulation of digestion, appetite control, and body weight, and is involved in neurogenesis via CCK-AR. There is some evidence to support that CCK and gastrin, via their receptors, are involved in promoting cancer development and progression, acting as growth and invasion factors.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 443906736  54 AMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAP---LERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15979  201 AKKRVIRMLVVIVAMFFLCWLPIFSANTWRAFDPLSAhraLSGAPISFIHLLSYTSACVNPLVY 264

tachykinin receptor and closely related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes G-protein coupled receptors for a variety of neuropeptides of the tachykinin (TK) family as well as closely related receptors. The tachykinins are widely distributed throughout the mammalian central and peripheral nervous systems and act as excitatory transmitters on neurons and cells in the gastrointestinal tract. The TKs are characterized by a common five-amino acid C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is a hydrophobic residue. The three major mammalian tachykinins are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). The physiological actions of tachykinins are mediated through three types of receptors: neurokinin receptor type 1 (NK1R), NK2R, and NK3R. SP is a high-affinity endogenous ligand for NK1R, which interacts with the Gq protein and activates phospholipase C, leading to elevation of intracellular calcium. NK2R is a high-affinity receptor for NKA, the tachykinin neuropeptide substance K. SP and NKA are found in the enteric nervous system and mediate in the regulation of gastrointestinal motility, secretion, vascular permeability, and pain perception. NK3R is activated by its high-affinity ligand, NKB, which is primarily involved in the central nervous system and plays a critical role in the regulation of gonadotropin hormone release and the onset of puberty.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  10 IAACQVLIFREIHASLVPGPSeragrrrrghrtGSPSEGAHVSAAmAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEA 89
Cdd:cd14992  186 MTLAYARISRELWFRKVPGFS------------IKEVERKRLKCK-RRVIKMLVCVVVLFVICWLPFHLFFLLRDFFPLI 252

                         90       100
                 ....*....|....*....|....*....
gi 443906736  90 PLE---RPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd14992  253 MKEkhtLQVYYFLHWIAMSNSMYNPIIYV 281

neuropeptide Y receptor-like found in insect and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes a novel G protein-coupled receptor (also known as PR4 receptor) from Drosophila melanogaster, which can be activated by the members of the neuropeptide Y (NPY) family, including NPY, peptide YY (PYY) and pancreatic polypeptide (PP), when expressed in Xenopus oocytes. These homologous peptides of 36-amino acids in length contain a hairpin-like structural motif, which referred to as the pancreatic polypeptide fold, and function as gastrointestinal hormones and neurotransmitters. The PR4 receptor also shares strong sequence homology to the mammalian tachykinin receptors (NK1R, NK2R, and NK3R), whose endogenous ligands are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), respectively. The tachykinins function as excitatory transmitters on neurons and cells in the gastrointestinal tract.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  52 SAAMAKTVRMTLVIVIVYVLCWAPFFLVQLwAAWDPEAPLERPPFVLLML----LASLNSCTNPWIY 114
Cdd:cd15392  211 AESKRKLVKMMITVVAIFALCWLPLNILNL-VGDHDESIYSWPYIPYLWLaahwLAMSHCCYNPFIY 276

melanin concentrating hormone receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Melanin-concentrating hormone receptor (MCHR) binds melanin concentrating hormone and is presumably involved in the neuronal regulation of food intake and energy homeostasis. Despite strong homology with somatostatin receptors, MCHR does not appear to bind somatostatin. Two MCHRs have been characterized in vertebrates, MCHR1 and MCHR2. MCHR1 is expressed in all mammals, whereas MCHR2 is only expressed in the higher order mammals, such as humans, primates, and dogs, and is not found in rodents. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  45 PSEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLwaawdPEAPLERPPFVLL------MLLASLNSCTNPWIYA 115
Cdd:cd15088  197 PGNQSHGSSRTKRVTKMVILIVVVFIVCWLPFHVVQL-----VNLAMNRPTLAFEvayflsICLGYANSCLNPFVYI 268

G protein-coupled receptor 150, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR150 is an orphan receptor closely related to the oxytocin and vasopressin receptors. Its endogenous ligand is not known. These receptors share a significant amino acid sequence similarity, suggesting that they have a common evolutionary origin.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 443906736  54 AMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15198  228 AKVKTLKMTLVIALLFVGCSLPYFIAELAAAFGSGDWEPEKVAAALGVMAVANSATNPFVF 288

dopamine 1-like receptor 2 from Drosophila melanogaster and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled dopamine 1-like receptor 2 is expressed in Drosophila heads and it shows significant sequence similarity with vertebrate and invertebrate dopamine receptors. Although the Drosophila Dop1R2 receptor does not cluster into the D1-like structural group, it does show pharmacological properties similar to D1-like receptors. As shown in vertebrate D1-like receptors, agonist stimulation of Dop1R2 activates adenylyl cyclase to increase cAMP levels and also generates a calcium signal through stimulation of phospholipase C.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  52 SAAMAKTVRMTLVIVI-VYVLCWAPFFLVQLWAAWDPEAPLERPPFV--LLMLLASLNSCTNPWIYA 115
Cdd:cd15067  186 AAAKEQKAAKTLGIVMgVFILCWLPFFVTNILIGFCPSNCVSNPDILfpLVTWLGYINSGMNPIIYA 252

urotensin-II receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The urotensin-II receptor (UII-R, also known as the hypocretin receptor) is a member of the class A rhodopsin-like G-protein coupled receptors, which binds the peptide hormone urotensin-II. Urotensin II (UII) is a vasoactive somatostatin-like or cortistatin-like peptide hormone. However, despite the apparent structural similarity to these peptide hormones, they are not homologous to UII. Urotensin II was first identified in fish spinal cord, but later found in humans and other mammals. In fish, UII is secreted at the back part of the spinal cord, in a neurosecretory centre called uroneurapophysa, and is involved in the regulation of the renal and cardiovascular systems. In mammals, urotensin II is the most potent mammalian vasoconstrictor identified to date and causes contraction of arterial blood vessels, including the thoracic aorta. The urotensin II receptor is a rhodopsin-like G-protein coupled receptor, which binds urotensin-II. The receptor was previously known as GPR14, or sensory epithelial neuropeptide-like receptor (SENR). The UII receptor is expressed in the CNS (cerebellum and spinal cord), skeletal muscle, pancreas, heart, endothelium and vascular smooth muscle. It is involved in the pathophysiological control of cardiovascular function and may also influence CNS and endocrine functions. Binding of urotensin II to the receptor leads to activation of phospholipase C, through coupling to G(q/11) family proteins. The resulting increase in intracellular calcium may cause the contraction of vascular smooth muscle.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 443906736  56 AKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPP----FVLLMLLASLNSCTNPWIY 114
Cdd:cd14999  209 QKVLKMIFTIVLVFWACFLPFWIWQLLYLYSPSLSLSPRTttyvNYLLTCLTYSNSCINPFLY 271

trace amine-associated receptor 1 and similar receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The trace amine-associated receptor 1 (TAAR1) is one of the 15 identified trace amine-associated receptor subtypes, which form a distinct subfamily within the class A G protein-coupled receptor family. Trace amines are endogenous amines of unknown function that have strong structural and metabolic similarity to classical monoamine neurotransmitters (serotonin, noradrenaline, adrenaline, dopamine, and histamine), which play critical roles in human and animal physiological activities such as cognition, consciousness, mood, motivation, perception, and autonomic responses. However, trace amines are found in the mammalian brain at very low concentrations compared to classical monoamines. TAAR1 is coupled to the Gs protein, which leads to activation of adenylate cyclase, and is thought to play functional role in the regulation of brain monoamines. TAAR1 is also shown to be activated by psychoactive compounds such as Ecstasy (MDMA), amphetamine and LSD. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  62 TLVIVI-VYVLCWAPFFLVQLwaaWDPEAPLERPP--FVLLMLLASLNSCTNPWIYA 115
Cdd:cd15314  219 TLAIVMgVFLLCWTPFFLCNI---IDPFINYSIPPvlIEVLNWLGYSNSTLNPFIYA 272

FMRFamide (Phe-Met-Arg-Phe) receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes Drosophila melanogaster G-protein coupled FMRFamide (Phe-Met-Arg-Phe-NH2) receptor DrmFMRFa-R and related invertebrate receptors, as well as the vertebrate proteins GPR139 and GPR142. DrmFMRFa-R binds with high affinity to FMRFamide and intrinsic FMRFamide-related peptides. FMRFamide is a neuropeptide from the family of FMRFamide-related peptides (FaRPs), which all containing a C-terminal RFamide (Arg-Phe-NH2) motif and have diverse functions in the central and peripheral nervous systems. FMRFamide is an important neuropeptide in many types of invertebrates such as insects, nematodes, molluscs, and worms. In invertebrates, the FMRFamide-related peptides are involved in the regulation of heart rate, blood pressure, gut motility, feeding behavior, and reproduction. On the other hand, in vertebrates such as mice, they play a role in the modulation of morphine-induced antinociception. Orphan receptors GPR139 and GPR142 are very closely related G protein-coupled receptors, but they have different expression patterns in the brain and in other tissues. These receptors couple to inhibitory G proteins and activate phospholipase C. Studies suggested that dimer formation may be required for their proper function. GPR142 is predominantly expressed in pancreatic beta-cells and mediates enhancement of glucose-stimulated insulin secretion, whereas GPR139 is mostly expressed in the brain and is suggested to play a role in the control of locomotor activity. Tryptophan and phenylalanine have been identified as putative endogenous ligands of GPR139.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLM---LLASLNSCTNPWIY 114
Cdd:cd14978  228 RTTIMLIAVVIVFLICNLPAGILNILEAIFGESFLSPIYQLLGDisnLLVVLNSAVNFIIY 288

beta adrenergic receptors (adrenoceptors), member of the class A family of seven-transmembrane G protein-coupled receptors; The beta adrenergic receptor (beta adrenoceptor), also known as beta AR, is activated by hormone adrenaline (epinephrine) and plays important roles in regulating cardiac function and heart rate, as well as pulmonary physiology. The human heart contains three subtypes of the beta AR: beta-1 AR, beta-2 AR, and beta-3 AR. Beta-1 AR and beta-2 AR, which expressed at about a ratio of 70:30, are the major subtypes involved in modulating cardiac contractility and heart rate by positively stimulating the G(s) protein-adenylate cyclase-cAMP-PKA signaling pathway. In contrast, beta-3 AR produces negative inotropic effects by activating inhibitory G(i) proteins. The aberrant expression of beta-ARs can lead to cardiac dysfunction such as arrhythmias or heart failure. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 443906736  64 VIVIVYVLCWAPFFLVQLWAAWDPEAPlERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15058  246 IIMGTFTLCWLPFFIANIINVFNRNLP-PGEVFLLLNWLGYINSGLNPIIY 295

bombesin receptor subfamily, member of the class A family of seven-transmembrane G protein-coupled receptors; This bombesin subfamily of G-protein coupled receptors consists of neuromedin B receptor (NMBR), gastrin-releasing peptide receptor (GRPR), and bombesin receptor subtype 3 (BRS-3). Bombesin is a tetradecapeptide, originally isolated from frog skin. Mammalian bombesin-related peptides are widely distributed in the gastrointestinal and central nervous systems. The bombesin family receptors couple mainly to the G proteins of G(q/11) family. NMBR functions as the receptor for the neuropeptide neuromedin B, a potent mitogen and growth factor for normal and cancerous lung and for gastrointestinal epithelial tissues. Gastrin-releasing peptide is an endogenous ligand for GRPR and shares high sequence homology with NMB in the C-terminal region. Both NMB and GRP possess bombesin-like biochemical properties. BRS-3 is classified as an orphan receptor and suggested to play a role in sperm cell division and maturation. BRS-3 interacts with known naturally-occurring bombesin-related peptides with low affinity; however, no endogenous high-affinity ligand to the receptor has been identified. The bombesin receptor family belongs to the seven transmembrane rhodopsin-like G-protein coupled receptors (class A GPCRs), which perceive extracellular signals and transduce them to guanine nucleotide-binding (G) proteins.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPF-----VLLMLLASLNSCTNP 111
Cdd:cd15927  221 KVAKTVLAFVVLFAVCWLPRHVFMLWFHFAPNGLVDYNAFwhvlkIVGFCLSFINSCVNP 280

GPRnna14 and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the orphan G-protein coupled receptor GPRnna14 found in body louse (Pediculus humanus humanus) as well as its closely related proteins of unknown function. These receptors are members of the class A rhodopsin-like G-protein coupled receptors. As an obligatory parasite of humans, the body louse is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. GPRnna14 shares significant sequence similarity with the members of the neurotensin receptor family. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 443906736  49 AHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWD----PEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15001  186 AYARDTRKQVIKMLISVVVLFAVCWGPLLIDNLLVSFDvistLHTQALKYMRIAFHLLSYANSCINPIIYA 256

alpha-1 adrenergic receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The alpha-1 adrenergic receptors (or adrenoceptors) are a subfamily of the class A rhodopsin-like GPCRs that share a common architecture of seven transmembrane helices. This subfamily consists of three highly homologous receptor subtypes that primarily mediate smooth muscle contraction: alpha-1A, alpha-1B, and alpha-1D. Activation of alpha-1 receptors by catecholamines such as norepinephrine and epinephrine couples to the G(q) protein, which then activates the phospholipase C pathway, leading to an increase in IP3 and calcium. Consequently, the elevation of intracellular calcium concentration leads to vasoconstriction in smooth muscle of blood vessels. In addition, activation of alpha-1 receptors by phenylpropanolamine (PPA) produces anorexia and may induce appetite suppression in rats.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 443906736  62 TLVIVI-VYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15062  197 TLGIVVgAFVLCWFPFFVVLPLGSLFSTLKPPEPVFKVVFWLGYFNSCLNPIIYP 251

somatostatin receptor type 3, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs) are composed of five distinct subtypes (SSTR1-5) that display strong sequence similarity with opioid receptors. All five receptor subtypes bind the natural somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. SSTR3 is coupled to inward rectifying potassium channels. SSTR3 plays critical roles in growth hormone secretion, endothelial cell cycle arrest and apoptosis. Furthermore, SSTR3 is expressed in the normal human pituitary and in nearly half of pituitary growth hormone adenomas.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQL--WAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15972  209 KVTRMVVIVVAAFVLCWLPFYALNIvnLVCPLPEEPSLFGLYFFVVVLSYANSCANPIIYG 269

trace amine-associated receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The trace amine-associated receptors (TAARs) are a distinct subfamily within the class A G protein-coupled receptor family. Trace amines are endogenous amines of unknown function that have strong structural and metabolic similarity to classical monoamine neurotransmitters (serotonin, noradrenaline, adrenaline, dopamine, and histamine), which play critical roles in human and animal physiological activities such as cognition, consciousness, mood, motivation, perception, and autonomic responses. However, trace amines are found in the mammalian brain at very low concentrations compared to classical monoamines. Trace amines, including p-tyramine, beta-phenylethylamine, and tryptamine, are also thought to act as chemical messengers to exert their biological effects in vertebrates. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 443906736  61 MTL-VIVIVYVLCWAPFFLVQLwaaWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15055  223 KTLgIVVGVFLLCWLPYYIVSL---VDPYISTPSSVFDVLIWLGYFNSCLNPLIYA 275

G protein-coupled estrogen receptor 1, member of the class A family of seven-transmembrane G protein-coupled receptors; G-protein coupled estrogen receptor 1 (GPER1), also known as the G-protein coupled receptor 30 (GPR30), is a high affinity receptor for estrogen. This receptor is a member of the class A of seven-transmembrane GPCRs. Estrogen binding results in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus. GPR30 plays an important role in development of tamoxifen resistance in breast cancer cells. The distribution of GPR30 is well established in the rodent, with high expression observed in the hypothalamus, pituitary gland, adrenal medulla, kidney medulla and developing follicles of the ovary. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 443906736  57 KTVRMTLVIVIVYVLCWAP---FFLVQLWAAWDPEAPLERPPFV--------LLMLLASLNSCTNPWIYA 115
Cdd:cd14989  197 KALRMILVVVLVFFICWLPenvFISIQLLQGTQEPSESYDESFRhnhpltghIVNLAAFSNSCLNPLIYS 266

G protein-coupled receptor 84 and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR84, also known as the inflammation-related G-Protein coupled receptor EX33, is a receptor for medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Among these medium-chain FFAs, capric acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0) are the most potent endogenous agonists of GPR84, whereas short-chain and long-chain saturated and unsaturated FFAs do not activate this receptor. GPR84 contains a [G/N]RY-motif instead of the highly conserved Asp-Arg-Tyr (DRY) motif found in the third transmembrane helix (TM3) of the rhodopsin-like class A receptors and important for efficient G protein-coupled signal transduction. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, which then activate the heterotrimeric G proteins. In the case of GPR84, activation of the receptor couples to a pertussis toxin sensitive G(i/o)-protein pathway. GPR84 knockout mice showed increased Th2 cytokine production including IL-4, IL-5, and IL-13 compared to wild-type mice. It has been also shown that activation of GPR84 augments lipopolysaccharide-stimulated IL-8 production in polymorphonuclear leukocytes and TNF-alpha production in macrophages, suggesting that GPR84 may function as a proinflammatory receptor.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 443906736  57 KTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLErppfVLLMLLASLNSCTNPWIYA 115
Cdd:cd15210  190 RLTRMMLVIFLCFLVCYLPITLVNVFDDEVAPPVLH----IIAYVLIWLSSCINPIIYV 244

alpha-2 adrenergic receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The alpha-2 adrenergic receptors (or adrenoceptors) are a subfamily of the class A rhodopsin-like GPCRs that share a common architecture of seven transmembrane helices. This subfamily consists of three highly homologous receptor subtypes that have a key role in neurotransmitter release: alpha-2A, alpha-2B, and alpha-2C. In addition, a fourth subtype, alpha-2D is present in ray-finned fishes and amphibians, but is not found in humans. The alpha-2 receptors are found in both central and peripheral nervous system and serve to produce inhibitory functions through the G(i) proteins. Thus, the alpha-2 receptors inhibit adenylate cyclase, which decreases cAMP production and thereby decreases calcium influx during the action potential. Consequently, lowered levels of calcium will lead to a decrease in neurotransmitter release by negative feedback. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  52 SAAMAKTVRMTLVIVIV---YVLCWAPFFLVQLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15059  185 RAAKRKERRFTLVLGVVmgaFVLCWLPFFFTYPLVVVCKTCGVPELLFKFFFWLGYCNSALNPVIYT 251

retinal pigment epithelium-derived rhodopsin homolog, member of the class A family of seven-transmembrane G protein-coupled receptors; Peropsin, also known as a retinal pigment epithelium-derived rhodopsin homolog (RRH), is a visual pigment-like protein found exclusively in the apical microvilli of the retinal pigment epithelium. Peropsin belongs to the type 2 opsin family of the class A G-protein coupled receptors. Peropsin presumably plays a physiological role in the retinal pigment epithelium either by detecting light directly or monitoring the levels of retinoids, the primary light absorber in visual perception, or other pigment-related compounds in the eye.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 443906736  60 RMTLVIVIVYVLCWAPFFLVQLWAA-WDPEaplERPPFVLLM--LLASLNSCTNPWIYA 115
Cdd:cd15073  215 KMSVIMIVMFLVAWSPYSIVCLWASfGEPK---KIPPWMAIIppLFAKSSTFYNPCIYV 270

D1-like family of dopamine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Dopamine receptors are members of the class A G protein-coupled receptors that are involved in many neurological processes in the central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous agonist for dopamine receptors. Dopamine receptors consist of at least five subtypes: D1, D2, D3, D4, and D5. The D1 and D5 subtypes are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 subtypes are members of the D2-like family. The D1-like family receptors are coupled to G proteins of the G(s) family, which activate adenylate cyclase, causing cAMP formation and activation of protein kinase A. In contrast, activation of D2-like family receptors is linked to G proteins of the G(i) family, which inhibit adenylate cyclase. Dopamine receptors are major therapeutic targets for neurological and psychiatric disorders such as drug abuse, depression, schizophrenia, or Parkinson's disease. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  45 PSEGAHVSAAMAKTVRMTL-VIVIVYVLCWAPFFLVQLWAAWDPEAPLERP-----PFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15057  214 PDSSLRSSLRRETKALKTLsIIMGVFVCCWLPFFILNCVLPFCDLRTAQFPcvpdtTFIVFVWLGWANSSLNPIIYA 290

neurokinin receptors (or tachykinin receptors), member of the class A family of seven-transmembrane G protein-coupled receptors; This group represents G-protein coupled receptors for a variety of neuropeptides of the tachykinin (TK) family. The tachykinins are widely distributed throughout the mammalian central and peripheral nervous systems and act as excitatory transmitters on neurons and cells in the gastrointestinal tract. The TKs are characterized by a common five-amino acid C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is a hydrophobic residue. The three major mammalian tachykinins are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). The physiological actions of tachykinins are mediated through three types of receptors: neurokinin receptor type 1 (NK1R), NK2R, and NK3R. SP is a high-affinity endogenous ligand for NK1R, which interacts with the Gq protein and activates phospholipase C, leading to elevation of intracellular calcium. NK2R is a high-affinity receptor for NKA, the tachykinin neuropeptide substance K. SP and NKA are found in the enteric nervous system and mediate in the regulation of gastrointestinal motility, secretion, vascular permeability, and pain perception. NK3R is activated by its high-affinity ligand, NKB, which is primarily involved in the central nervous system and plays a critical role in the regulation of gonadotropin hormone release and the onset of puberty.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 443906736  53 AAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPE---APLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15390  214 RAKRKVVKMMIVVVVIFAICWLPYHLYFILTYLYPDinsWKYIQQIYLAIYWLAMSNSMYNPIIY 278

nociceptin/orphanin FQ peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The nociceptin (NOP) receptor binds nociceptin or orphanin FQ, a 17 amino acid endogenous neuropeptide. The NOP receptor is involved in the modulation of various brain activities including instinctive and emotional behaviors. The opioid receptor family is composed of four major subtypes: mu (MOP), delta (DOP), kappa (KOP) opioid receptors, and the nociceptin/orphanin FQ peptide receptor (NOP). They are distributed widely in the central nervous system and respond to classic alkaloid opiates, such as morphine and heroin, as well as to endogenous peptide ligands, which include dynorphins, enkephalins, endorphins, endomorphins, and nociceptin. Opioid receptors are coupled to inhibitory G proteins of the G(i/o) family and involved in regulating a variety of physiological functions such as pain, addiction, mood, stress, epileptic seizure, and obesity, among many others.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 443906736  57 KTVRMTLVIVIVYVLCWAP---FFLVQLWAAwDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15092  209 RITRLVLVVVAVFVGCWTPiqiFVLAQGLGV-QPSSETAVAILRFCTALGYVNSSLNPVLYA 269

serotonin receptor subtype 7, member of the class A family of seven-transmembrane G protein-coupled receptors; The 5-HT7 receptor, one of 14 mammalian serotonin receptors, is a member of the class A of GPCRs and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). 5-HT7 receptor mainly couples to Gs protein, which positively stimulates adenylate cyclase, leading to increased intracellular cAMP formation and calcium influx. 5-HT7 receptor is expressed in various human tissues, mainly in the brain, the lower gastrointestinal tract and in vital blood vessels including the coronary artery. In the CNS, serotonin is involved in the regulation of appetite, mood, sleep, cognition, learning and memory, as well as implicated in neurologic disorders such as migraine, schizophrenia, and depression.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 443906736  62 TL-VIVIVYVLCWAPFFLVQL---WAAWDPEAPLERPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd15329  193 TLgIIMGAFTLCWLPFFILALlrpFLKPIKCSCIPLWLSRLFLWLGYANSFLNPIIYA 250

angiotesin receptor family and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the angiotensin receptors, the bradykinin receptors, apelin receptor as well as putative G-protein coupled receptors (GPR15 and GPR25). Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors. Ang II contributes to cardiovascular diseases such as hypertension and atherosclerosis via AT1R activation. Ang II increases blood pressure through Gq-mediated activation of phospholipase C, resulting in phosphoinositide (PI) hydrolysis and increased intracellular calcium levels. Through the AT2 receptor, Ang II counteracts the vasoconstrictor action of AT1R and thereby induces vasodilation, sodium excretion, and reduction of blood pressure. Bradykinins (BK) are pro-inflammatory peptides that mediate various vascular and pain responses to tissue injury through its B1 and B2 receptors. Apelin (APJ) receptor binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body, and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake. Orphan receptors, GPR15 and GPR25, share strong sequence homology to the angiotensin II type AT1 and AT2 receptors.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 443906736  57 KTVRMTLVIVIVYVLCWAPF-------FLVQL--WAAWDPEAPLeRPPFVLLMLLASLNSCTNPWIYA 115
Cdd:cd14985  208 KSLKIIFALVVAFLVCWLPFhffkfldFLAQLgaIRPCFWELFL-DLGLPIATCLAFTNSCLNPFIYV 274

non-visual parapinopsin, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the non-visual pineal pigment, parapinopsin, which is a member of the class A of the seven transmembrane G protein-coupled receptors. Parapinopsin serves as a UV-sensitive pigment for the wavelength discrimination in the pineal-related organs of lower vertebrates such as reptiles, amphibians, and fish. Although parapinopsin is phylogenetically related to vertebrate visual pigments such as rhodopsin, which releases its retinal chromophore and bleaches, the parapinopsin photoproduct is stable and does not bleach. The vertebrate non-visual opsin family includes pinopsins, parapinopsin, VA (vertebrate ancient) opsins, and parietopsins. These non-visual opsins are expressed in various extra-retinal tissues and/or in non-rod, non-cone retinal cells.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 443906736  47 EGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15075  201 EGGSTAKAEVQVARMVVVMVMAFLLCWLPYAAFALTVVSKPDVYINPLIATVPMYLAKSSTVYNPIIY 268

leucokinin-like peptide receptor from tick and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes a leucokinin-like peptide receptor from the Southern cattle tick, Boophilus microplus, a pest of cattle world-wide. Leucokinins are invertebrate neuropeptides that exhibit myotropic and diuretic activity. This receptor is the first neuropeptide receptor known from the Acari and the second known in the subfamily of leucokinin-like peptide G-protein-coupled receptors. The other known leucokinin-like peptide receptor is a lymnokinin receptor from the mollusc Lymnaea stagnalis.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 443906736  46 SEGAHVSAAMAKTVRMTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPPFVLLML---LASLNSCTNPWIYA 115
Cdd:cd15393  206 VRDDEILKNKKKVIKMLIIVVALFALCWLPLQTYNLLNEIKPEINKYKYINIIWFCshwLAMSNSCYNPFIYG 278

melatonin receptor 1, member of the class A family of seven-transmembrane G protein-coupled receptors; Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring sleep-promoting chemical found in vertebrates, invertebrates, bacteria, fungi, and plants. In mammals, melatonin is secreted by the pineal gland and is involved in regulation of circadian rhythms. Its production peaks during the nighttime, and is suppressed by light. Melatonin is shown to be synthesized in other organs and cells of many vertebrates, including the Harderian gland, leukocytes, skin, and the gastrointestinal (GI) tract, which contains several hundred times more melatonin than the pineal gland and is involved in the regulation of GI motility, inflammation, and sensation. Melatonin exerts its pleiotropic physiological effects through specific membrane receptors, named MT1A, MT1B, and MT1C, which belong to the class A rhodopsin-like G-protein coupled receptor family. MT1A and MT1B subtypes are present in mammals, whereas MT1C subtype has been found in amphibians and birds. The melatonin receptors couple to G proteins of the G(i/o) class, leading to the inhibition of adenylate cyclase.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 443906736  61 MTLVIVIVYVLCWAPFFLVQLWAAWDPEAPLERPP---FVLLMLLASLNSCTNPWIY 114
Cdd:cd15209  212 TMFVVFVLFAVCWAPLNFIGLAVAINPKEMAPKIPewlFVASYFMAYFNSCLNAIIY 268

alpha-2 adrenergic receptors subtype B, member of the class A family of seven-transmembrane G protein-coupled receptors; The alpha-2 adrenergic receptors (or adrenoceptors) are a subfamily of the class A rhodopsin-like GPCRs that share a common architecture of seven transmembrane helices. This subfamily consists of three highly homologous receptor subtypes that have a key role in neurotransmitter release: alpha-2A, alpha-2B, and alpha-2C. In addition, a fourth subtype, alpha-2D is present in ray-finned fishes and amphibians, but is not found in humans. The alpha-2 receptors are found in both central and peripheral nervous system and serve to produce inhibitory functions through the G(i) proteins. Thus, the alpha-2 receptors inhibit adenylate cyclase, which decreases cAMP production and thereby decreases calcium influx during the action potential. Consequently, lowered levels of calcium will lead to a decrease in neurotransmitter release by negative feedback.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 443906736  64 VIVIVYVLCWAPFFLVQLWAAWDPE-APLERPPFVLLMLLASLNSCTNPWIY 114
Cdd:cd15321  206 VVIGVFVLCWFPFFFSYSLGAICPElCKVPHSLFQFFFWIGYCNSSLNPVIY 257

D2-like dopamine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Dopamine receptors are members of the class A G protein-coupled receptors that are involved in many neurological processes in the central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous agonist for dopamine receptors. Dopamine receptors consist of at least five subtypes: D1, D2, D3, D4, and D5. The D1 and D5 subtypes are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 subtypes are members of the D2-like family. The D1-like family receptors are coupled to G proteins of the G(s) family, which activate adenylate cyclase, causing cAMP formation and activation of protein kinase A. In contrast, activation of D2-like family receptors is linked to G proteins of the G(i) family, which inhibit adenylate cyclase. Dopamine receptors are major therapeutic targets for neurological and psychiatric disorders such as drug abuse, depression, schizophrenia, or Parkinson's disease.

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                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 443906736  62 TLVIVI-VYVLCWAPFFLVQLWAAWDP--EAPLERPPFVLLML---LASLNSCTNPWIY 114
Cdd:cd15053  194 TLAIVLgVFLFCWLPFFTLNILNAICPklQNQSCHVGPALFSLttwLGYVNSFLNPIIY 252