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
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15975   1 YINTVLSCIIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYIVIDIPINVYKL 61

endothelin A (or endothelin-1) receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C, and phospholipase D, as well as cytosolic protein kinase activation. They play an important role in the regulation of the cardiovascular system and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels. Two endothelin receptor subtypes have been isolated and identified in vertebrates, endothelin A receptor (ET-A) and endothelin B receptor (ET-B), and are members of the seven transmembrane class A G-protein coupled receptor family which activate multiple effectors via different types of G protein. Some vertebrates contain a third subtype, endothelin A receptor (ET-C). ET-A receptors are mainly located on vascular smooth muscle cells, whereas ET-B receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15975   1 YINTVLSCIIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYIVIDIPINVYKL 61

endothelin A (or endothelin-1) receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C, and phospholipase D, as well as cytosolic protein kinase activation. They play an important role in the regulation of the cardiovascular system and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels. Two endothelin receptor subtypes have been isolated and identified in vertebrates, endothelin A receptor (ET-A) and endothelin B receptor (ET-B), and are members of the seven transmembrane class A G-protein coupled receptor family which activate multiple effectors via different types of G protein. Some vertebrates contain a third subtype, endothelin A receptor (ET-C). ET-A receptors are mainly located on vascular smooth muscle cells, whereas ET-B receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15975   1 YINTVLSCIIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYIVIDIPINVYKL 61

endothelin C receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Endothelins are able to activate a number of signal transduction processes including phospholipase A2, phospholipase C, and phospholipase D, as well as cytosolic protein kinase activation. They play an important role in the regulation of the cardiovascular system and are the most potent vasoconstrictors identified, stimulating cardiac contraction, regulating the release of vasoactive substances, and stimulating mitogenesis in blood vessels. Two endothelin receptor subtypes have been isolated and identified in vertebrates, endothelin A receptor (ET-A) and endothelin B receptor (ET-B), and are members of the seven transmembrane class A G-protein coupled receptor family which activate multiple effectors via different types of G protein. Some vertebrates contain a third subtype, endothelin A receptor (ET-C). ET-A receptors are mainly located on vascular smooth muscle cells, whereas ET-B receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain. The ET-C receptor is specific for endothelin-3 on frog dermal melanophores; its activation causes dispersion of pigment granules.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15977   1 YVNTILSCVIFLVGIIGNSTLLRIIYKNKCMRNGPNVLIASLALGDLLYILIAIPINVIKL 61

endothelin receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily of G-protein coupled receptors includes endothelin receptors, bombesin receptor subtype 3 (BRS-3), gastrin-releasing peptide receptor (GRPR), neuromedin B receptor (NMB-R), endothelin B receptor-like 2 (ETBR-LP-2), and GRP37. The endothelin receptors and related proteins are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family (class A GPCRs) which activate multiple effectors via different types of G protein.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFK 89
Cdd:cd14977   1 YVIMSLSLVIFAVGIIGNLMVLCIVCTNYYMRSVPNILIASLALGDLLLLLLCVPLNAYN 60

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVF 88
Cdd:cd00637   2 AVLYILIFVVGLVGNLLVILVILRNRRLRTVTNYFILNLAVADLLVGLLVIPFSLV 57

neuromedin B receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The neuromedin B receptor (NMBR), also known as BB1, is a G-protein coupled receptor whose endogenous ligand is the neuropeptide neuromedin B. Neuromedin B is a potent mitogen and growth factor for normal and cancerous lung and for gastrointestinal epithelial tissues. NMBR is widely distributed in the CNS, with especially high levels in olfactory nucleus and thalamic regions. The receptor couples primarily to a pertussis-toxin-insensitive G protein of the Gq/11 family, which leads to the activation of phospholipase C. NMBR belongs to the bombesin subfamily of G-protein coupled receptors, whose members also include gastrin-releasing peptide receptor (GRPR) and bombesin receptor subtype 3 (BRS-3). Bombesin is a tetradecapeptide, originally isolated from frog skin.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 2746075   39 IFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFK 89
Cdd:cd15125  10 IITVGLLGNITLVKIFITNSAMRSVPNIFISSLAAGDLLLLVTCVPVDASR 60

prokineticin receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Prokineticins 1 (PROK1) and 2 (PROK2), also known as endocrine gland vascular endothelial factor and Bombina varigata 8, respectively, are multifunctional chemokine-like peptides that are highly conserved across species. Prokineticins can bind with similar affinities to two closely homologous 7-transmembrane G protein coupled receptors, PROKR1 and PROKR2, which are phylogenetically related to the tachykinin receptors. Prokineticins and their GPCRs are widely distributed in human tissues and are involved in numerous physiological roles, including gastrointestinal motility, generation of circadian rhythms, neuron migration and survival, pain sensation, angiogenesis, inflammation, and reproduction. Moreover, different point mutations in genes encoding PROK2 or its receptor (PROKR2) can lead to Kallmann syndrome, a disease characterized by delayed or absent puberty and impaired olfactory function.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 2746075   31 INTVISCTIFIVGmVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINV 87
Cdd:cd15204   3 LGVVYVLIMLVCG-VGNLLLIAVLARYKKLRTLTNLLIANLALSDFLVAVFCLPFEM 58

G protein-coupled receptor 37, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR37, also called parkin-associated endothelin-like receptor (Pael-R), was isolated from a set of human brain frontal lobe expressed sequence tags. It is highly expressed in the mammalian CNS. It is a substrate of parkin and is involved in the pathogenesis of Parkinson's disease. GPR37 has recently been shown to act as a receptor for the neuropeptide prosaptide, the active fragment of the secreted neuroprotective and glioprotective factor prosaposin (also called sulfated glycoprotein-1). Both prosaptide and prosaposin protect primary astrocytes against oxidative stress. GPR37 is part of the class A family of GPCRs that includes receptors for hormones, neurotransmitters, sensory stimuli, 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVF 88
Cdd:cd15127   1 YAVMCLSVVIFGIGIMGNVAVMCIVCHNYYMRSISNSLLANLAFWDFLIIFFCLPLVIF 59

neuromedin U receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Neuromedin U (NMU) is a highly conserved neuropeptide with a common C-terminal heptapeptide sequence (FLFRPRN-amide) found at the highest levels in the gastrointestinal tract and pituitary gland of mammals. Disruption or replacement of residues in the conserved heptapeptide region can result in the reduced ability of NMU to stimulate smooth-muscle contraction. Two G-protein coupled receptor subtypes, NMU-R1 and NMU-R2, with a distinct expression pattern, have been identified to bind NMU. NMU-R1 is expressed primarily in the peripheral nervous system, while NMU-R2 is mainly found in the central nervous system. Neuromedin S, a 36 amino-acid neuropeptide that shares a conserved C-terminal heptapeptide sequence with NMU, is a highly potent and selective NMU-R2 agonist. Pharmacological studies have shown that both NMU and NMS inhibit food intake and reduce body weight, and that NMU increases energy expenditure.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 2746075   39 IFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15133  10 IFVVGVVGNVLTCLVIARHKAMRTPTNYYLFSLAVSDLLVLLLGMPLELYEL 61

neuropeptide capa receptor and similar invertebrate proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; CapaR is a G-protein coupled receptor for the Drosophila melanogaster capa neuropeptides (Drm-capa-1 and -2), which act on the Malpighian tubules to increase fluid transport. The capa peptides are evolutionarily related to vertebrate Neuromedin U neuropeptide and contain a C-terminal FPRXamide motif. CapaR regulates fluid homeostasis through its ligands, thereby acts as a desiccation stress-responsive receptor. CapaR undergoes desensitization, with internalization mediated by beta-arrestin-2.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVFKV 90
Cdd:cd15134   4 TIIYGIIFVTGVVGNLCTCIVIARNRSMHTATNYYLFSLAVSDLLLLILGLPFELYTI 61

neurotensin receptors and related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes the neurotensin receptors and related G-protein coupled receptors, including neuromedin U receptors, growth hormone secretagogue receptor, motilin receptor, the putative GPR39 and the capa receptors from insects. These receptors all bind peptide hormones with diverse physiological effects. 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 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVF 88
Cdd:cd14979   4 TAIYVAIFVVGIVGNLLTCIVIARHKSLRTTTNYYLFSLAVSDLLILLVGLPVELY 59

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
                ....*....|....*....|....*....|....*....|....*...
gi 2746075   38 TIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPI 85
Cdd:cd15001   8 ITFVLGLIGNSLVIFVVARFRRMRSVTNVFLASLATADLLLLVFCVPL 55

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 2746075   31 INTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPIN 86
Cdd:cd14992   2 ILGVALVVIILVSVVGNFIVIAALARHKNLRGATNYFIASLAISDLLMALFCTPFN 57

pyroglutamylated RFamide peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; 26RFa, also known as QRFP (Pyroglutamylated RFamide peptide), is a 26-amino acid residue peptide that belongs to a family of neuropeptides containing an Arg-Phe-NH2 (RFamide) motif at its C-terminus. 26Rfa/QRFP 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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2746075   33 TVISCT-IFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINvfkvqsscLLESCSGNW 103
Cdd:cd15205   3 FVITYVlIFVLALFGNSLVIYVVTRKRAMRTATNIFICSLALSDLLITFFCIPFT--------LLQNISSNW 66

endothelin B receptor-like protein 2, member of the class A family of seven-transmembrane G protein-coupled receptors; Endothelin B receptor-like protein 2, also called GPR37L1, is almost exclusively expressed in the nervous system. It has recently been shown to act as a receptor for the neuropeptide prosaptide, the active fragment of the secreted neuroprotective and glioprotective factor prosaposin (also called sulfated glycoprotein-1). Both prosaptide and prosaposin protect primary astrocytes against oxidative stress. GPR37L1 is part of the class A family of GPCRs that includes receptors for hormones, neurotransmitters, sensory stimuli, 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 2746075   35 ISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVF 88
Cdd:cd15126   6 LALVVFAVGIVGNLSVMCIVWHSYYLKSAWNSILASLALWDFLVLFFCLPVVVF 59

type 2 opsins in animals, member of the class A family of seven-transmembrane G protein-coupled receptors; This rhodopsin family represents the type 2 opsins found in vertebrates and invertebrates except sponge. Type 2 opsins primarily function as G protein coupled receptors and are responsible for vision as well as for circadian rhythm and pigment regulation. On the contrary, type 1 opsins such as bacteriorhodopsin and proteorhodopsin are found in both prokaryotic and eukaryotic microbes, functioning as light-gated ion channels, proton pumps, sensory receptors and in other unknown functions. Although these two opsin types share seven-transmembrane domain topology and a conserved lysine reside in the seventh helix, type 1 opsins do not activate G-proteins and are not evolutionarily related to type 2. Type 2 opsins can be classified into six distinct subfamilies including the vertebrate opsins/encephalopsins, the G(o) opsins, the G(s) opsins, the invertebrate G(q) opsins, the photoisomerases, and the neuropsins.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPI 85
Cdd:cd14969   1 YVLAVYLSLIGVLGVVLNGLVIIVFLKKKKLRTPLNLFLLNLALADLLMSVVGYPL 56

neuropeptide Y receptor type 4, member of the class A family of seven-transmembrane G protein-coupled receptors; NPY is a 36-amino acid peptide neurotransmitter with a C-terminal tyrosine amide residue that is widely distributed in the brain and the autonomic nervous system of many mammalian species. NPY exerts its functions through five, G-protein coupled receptor subtypes including NPY1R, NPY2R, NPY4R, NPY5R, and NPY6R; however, NPY6R is not functional in humans. NYP receptors are also activated by its two other family members, peptide YY (PYY) and pancreatic polypeptide (PP). They typically couple to G(i) or G(o) proteins, which leads to a decrease in adenylate cyclase activity, thereby decreasing intracellular cAMP levels, and are involved in diverse physiological roles including appetite regulation, circadian rhythm, and anxiety.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 2746075   37 CTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINV 87
Cdd:cd15397   8 SLVMAVGLLGNICLICVIARQKEKTNVTNILIANLSFSDILVCLVCLPFTV 58

G protein-coupled receptor PSP24 and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes two human orphan receptors, GPR45 and GPR65, and their closely related proteins found in vertebrates and invertebrates. GPR45 and GPR 65 are also called PSP24-alpha (or PSP24-1) and PSP24-beta (or PSP24-2) in other vertebrates, respectively. These receptors exhibit the highest sequence homology to each other. PSP24 was originally identified as a novel, high-affinity lysophosphatidic acid (LPA) receptor in Xenopus laevis oocytes; however, PSP24 receptors (GPR45 and GPR63) have not been shown to be activated by LPA. Instead, sphingosine 1-phosphate and dioleoylphosphatidic acid have been shown to act as low affinity agonists for GPR63. PSP24 receptors are highly expressed in neuronal cells of cerebellum and their expression level remains constant from the early embryonic stages to adulthood, suggesting the important role of PSP24s in brain neuronal functions. Members of this subgroup contain the highly conserved Asp-Arg-Tyr/Phe (DRY/F) motif found in the third transmembrane helix (TM3) of the rhodopsin-like class A receptors which is 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, 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 2746075   34 VISCTIFIvGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd15213   6 LMILMIFV-GFLGNSIVCLIVYQKPAMRSAINLLLANLAFSDIMLSLVCMP 55

ecdysis-triggering hormone receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup represents the ecdysis-triggering hormone receptors found in insects, which are members of the class A family of seven-transmembrane G-protein coupled receptors. Ecdysis-triggering hormones are vital regulatory signals that govern the stereotypic physiological sequence leading to cuticle shedding in insects. Thus, the ETH signaling system has been a target for the design of more sophisticated insect-selective pest control strategies. Two subtypes of ecdysis-triggering hormone receptor were identified in Drosophila melanogaster. Blood-borne ecdysis-triggering hormone (ETH) activates the behavioral sequence through direct actions on the central nervous system. In insects, ecdysis is thought to be controlled by the interaction between peptide hormones; in particular between ecdysis-triggering hormone (ETH) from the periphery and eclosion hormone (EH) and crustacean cardioactive peptide (CCAP) from the central nervous system. 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 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd14997   4 SVVYGVIFVVGVLGNVLVGIVVWKNKDMRTPTNIFLVNLSVADLLVLLVCMP 55

putative neuropeptide receptor BNGR-A34 and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes putative neuropeptide receptor BNGR-A34 found in silkworm and its closely related proteins from invertebrates. They are members of the class A rhodopsin-like GPCRs, which represent 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. 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 2746075   31 INTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVI 81
Cdd:cd15000   1 IKSSMFLPVVLFGIFGNFVLLYILASNRSLRTPTNLLIGNMALADLLTLLV 51

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 2746075   30 YINTVISCTIFIVGMVGNATLLrIIYQNKCMRNGPNALIASLALGDLIYVVIDLPI 85
Cdd:cd14978   1 VLYGYVLPVICIFGIIGNILNL-VVLTRKSMRSSTNVYLAALAVSDILVLLSALPL 55

G protein-coupled receptor 63, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes the human orphan receptor GPR63, which is also called PSP24-beta or PSP24-2, and its closely related proteins found in vertebrates. GPR63 shares the highest sequence homology with GPR45 (Xenopus PSP24, mammalian PSP24-alpha or PSP24-1). PSP24 was originally identified as a novel, high-affinity lysophosphatidic acid (LPA) receptor in Xenopus laevis oocytes; however, PSP24 receptors (GPR45 and GPR63) have not been shown to be activated by LPA. Mammalian PSP24 receptors are highly expressed in neuronal cells of cerebellum and their expression level remains constant from the early embryonic stages to adulthood, suggesting the important role of PSP24s in brain neuronal functions. Members of this subgroup contain the highly conserved Asp-Arg-Tyr/Phe (DRY/F) motif found in the third transmembrane helix (TM3) of the rhodopsin-like class A receptors which is 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, 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
                ....*....|....*....|....*....|....*....|....*.
gi 2746075   39 IFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd15404  10 ILLVSFLGNFVVCLMVYQKAAMRSAINILLASLAFADMMLAVLNMP 55

prolactin-releasing peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Prolactin-releasing peptide (PrRP) receptor (previously known as GPR10) is expressed in the central nervous system with the highest levels located in the anterior pituitary and is activated by its endogenous ligand PrRP, a neuropeptide possessing a C-terminal Arg-Phe-amide motif. There are two active isoforms of PrRP in mammals: one consists of 20 amino acids (PrRP-20) and the other consists of 31 amino acids (PrRP-31), where PrRP-20 is a C-terminal fragment of PrRP-31. Binding of PrRP to the receptor coupled to G(i/o) proteins activates the extracellular signal-related kinase (ERK) and it can also couple to G(q) protein leading to an increase in intracellular calcium and activation of c-Jun N-terminal protein kinase (JNK). The PrRP receptor shares significant sequence homology with the neuropeptide Y (NPY) receptor, and micromolar levels of NPY can bind and completely inhibit the PrRP-evoked intracellular calcium response in PrRP receptor-expressing cells, suggesting that the PrRP receptor shares a common ancestor with the NPY receptors. PrRP has been shown to reduce food intake and body weight and modify body temperature when administered in rats. It also has been shown to decrease circulating growth hormone levels by activating somatostatin-secreting neurons in the hypothalamic periventricular nucleus.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 2746075   38 TIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINVF 88
Cdd:cd15394   9 LVVLVGVVGNYLLIYVICRTKKMHNVTNFLIGNLAFSDMLMCATCVPLTLA 59

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
                ....*....|....*....|....*....|....*....|....*....|....*
gi 2746075   30 YINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd15384   1 LLKIVVLAVMFVISFIGNLLTIIQIYRLRRSRRTIYSLLLHLAIADLLVTFFCIP 55

G protein-coupled receptor 45, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes the human orphan receptor GPR45 and closely related proteins found in vertebrates. GPR45 is also called PSP24 in Xenopus and PSP24-alpha (or PSP24-1) in mammals. GPR45 shows the highest sequence homology with GPR63 (PSP24-beta, or PSP24-2). PSP24 was originally identified as a novel, high-affinity lysophosphatidic acid (LPA) receptor in Xenopus laevis oocytes; however, PSP24 receptors (GPR45 and GPR63) have not been shown to be activated by LPA. Mammalian PSP24 receptors are highly expressed in neuronal cells of cerebellum and their expression level remains constant from the early embryonic stages to adulthood, suggesting the important role of PSP24s in brain neuronal functions. Members of this subgroup contain the highly conserved Asp-Arg-Tyr/Phe (DRY/F) motif found in the third transmembrane helix (TM3) of the rhodopsin-like class A receptors which is 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, 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 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd15403   4 AIVMILMIAIGFLGNAIVCLIVYQKPAMRSAINLLLATLAFSDIMLSLLCMP 55

cholecystokinin receptor type A, 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
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 2746075   31 INTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPINV 87
Cdd:cd15978   2 VRILLYSLIFLLSVLGNSLIIAVLIRNKRMRTVTNIFLLSLAVSDLMLCLFCMPFTL 58

growth hormone secretagogue receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Growth hormone secretagogue receptor, GHSR, is also known as GH-releasing peptide receptor (GHRP) or Ghrelin receptor. Ghrelin, the endogenous ligand for GHSR, is an acylated 28-amino acid peptide hormone produced by ghrelin cells in the gastrointestinal tract. Ghrelin, also called hunger hormone, is involved in the regulation of growth hormone release, appetite and feeding, gut motility, lipid and glucose metabolism, and energy balance. It also plays a role in the cardiovascular, immune, and reproductive systems. GHSR couples to G-alpha-11 proteins. Both ghrelin and GHSR are expressed in a wide range of cancer tissues. Recent studies suggested that ghrelin may play a role in processes associated with cancer progression, including cell proliferation, metastasis, apoptosis, and angiogenesis.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 2746075   33 TVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIyVVIDLPINVFKV 90
Cdd:cd15131   4 TVTCVLLFVVGVTGNLMTMLVVSKYRDMRTTTNLYLSSMAFSDLL-IFLCMPLDLYRL 60

melatonin receptor subtype 1A, 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 2746075   41 IVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDLIYVVIDLPI 85
Cdd:cd15402  12 VVDILGNLLVILSVYRNKKLRNAGNIFVVSLAVADLVVAIYPYPL 56

galanin receptor subtype 1, member of the class A family of seven-transmembrane G protein-coupled receptors; The G protein-coupled galanin receptors bind galanin, a neuropeptide that is widely expressed in the brain, peripheral tissues, and endocrine glands. Three receptors subtypes have been so far identified: GAL1, GAL2, and GAL3. The specific functions of each subtype remains mostly unknown, although galanin is thought to be involved in a variety of neuronal functions such as hormone release and food intake. Galanin is implicated in numerous neurological and psychiatric diseases including Alzheimer's disease, depression, eating disorders, epilepsy and stroke, among many others.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 2746075   39 IFIVGMVGNATLLRIIYQNKCM--RNGPNALIASLALGDLIYVVIDLP 84
Cdd:cd15098  10 IFCLGVLGNSLVITVLARVKPGkrRSTTNVFILNLSIADLFFLLFCVP 57