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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  58 NNLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15078    17 NNLLVLILYYKFKRLRTPTNLLLVNISLSDLLVSLLGVTFTFMSCVRGRWVFDVAGCVWDGFSNSLFGIVS 87

encephalopsins (opsin-3), member of the class A family of seven-transmembrane G protein-coupled receptors; Encephalopsin, also called Opsin-3 or Panopsin, is a mammalian extra-retinal opsin that is highly localized in the brain. It is thought to play a role in encephalic photoreception. Encephalopsin belongs to the class A of the G protein-coupled receptors and shows strong homology to the vertebrate visual opsins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  58 NNLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15078    17 NNLLVLILYYKFKRLRTPTNLLLVNISLSDLLVSLLGVTFTFMSCVRGRWVFDVAGCVWDGFSNSLFGIVS 87

encephalopsins (opsin-3), member of the class A family of seven-transmembrane G protein-coupled receptors; Encephalopsin, also called Opsin-3 or Panopsin, is a mammalian extra-retinal opsin that is highly localized in the brain. It is thought to play a role in encephalic photoreception. Encephalopsin belongs to the class A of the G protein-coupled receptors and shows strong homology to the vertebrate visual opsins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  58 NNLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15078    17 NNLLVLILYYKFKRLRTPTNLLLVNISLSDLLVSLLGVTFTFMSCVRGRWVFDVAGCVWDGFSNSLFGIVS 87

teleost multiple tissue (tmt) opsin, member of the class A family of seven-transmembrane G protein-coupled receptors; Teleost multiple tissue (tmt) opsins are homologs of encephalopsin. Mouse encephalopsin (or panopsin) is highly expressed in the brain and testes, whereas the teleost homologs are localized to multiple tissues. The exact functions of the encephalopsins and tmt-opsins are unknown. 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. They are thought to be involved in light-dependent physiological functions such as photo-entrainment of circadian rhythm, photoperiodicity and body color change. Tmt opsins belong to the class A of the G protein-coupled receptors and show strong homology to the vertebrate visual opsins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  58 NNLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15086    17 NNLLVLVLFCKYKVLRSPINLLLLNISLSDLLVCVLGTPFSFAASTQGRWLIGEHGCRWYGFANSLFGIVS 87

neuropsin (Opsin-5), member of the class A family of seven-transmembrane G protein-coupled receptors; Neuropsin, also known as Opsin-5, is a photoreceptor protein expressed in the retina, brain, testes, and spinal cord. Neuropsin belongs to the type 2 opsin family of the class A G-protein coupled receptors. Mammalian neuropsin activates Gi protein-mediated photo-transduction pathway in a UV-dependent manner, whereas, in non-mammalian vertebrates, neuropsin is involved in regulating the photoperiodic control of seasonal reproduction in birds such as quail. As with other opsins, it may also act as a retinal photoisomerase.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15074    18 NGTVLFVLYRRRSKLKPAELLTVNLAVSDLGISVFGYPLAIISAFAHRWLFGDIGCVFYGFCGFLFGCCS 87

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd00637    16 NLLVILVILRNRRLRTVTNYFILNLAVADLLVGLLVIPFSLVSLLLGRWWFGDALCKLLGFLQSVSLLAS 85

invertebrate Gq opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; The invertebrate Gq-coupled opsin subfamily includes the arthropod and mollusc visual opsins. Like the vertebrate visual opsins, arthropods possess color vision by the use of multiple opsins sensitive to different light wavelengths. The invertebrate Gq opsins are closely related to the vertebrate melanopsins, the primary photoreceptor molecules for non-visual responses to light, and the R1-R6 photoreceptors, which are the fly equivalent to the vertebrate rods. The Gq opsins belong the class A of the G protein-coupled receptors and possess seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLF-GVTFTFVSCLRNGWVWDTVGCVWDGFSGSLF 124
Cdd:cd15337    18 NLLVIYLFSKTKSLRTPSNMFIINLAISDFGFSAVnGFPLKTISSFNKKWIWGKVACELYGFAGGIF 84

amine receptors and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; Amine receptors of the class A family of GPCRs include adrenoceptors, 5-HT (serotonin) receptors, muscarinic cholinergic receptors, dopamine receptors, histamine receptors, and trace amine receptors. The receptors of amine subfamily are major therapeutic targets for the treatment of neurological disorders and psychiatric diseases. 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 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC-VW 116
Cdd:cd14967    17 NLLVILAVYRNRRLRTVTNYFIVSLAVADLLVALLVMPFSAVYTLLGYWPFGPVLCrFW 75

7 transmembrane receptor (rhodopsin family); This family contains, amongst other G-protein-coupled receptors (GCPRs), members of the opsin family, which have been considered to be typical members of the rhodopsin superfamily. They share several motifs, mainly the seven transmembrane helices, GCPRs of the rhodopsin superfamily. All opsins bind a chromophore, such as 11-cis-retinal. The function of most opsins other than the photoisomerases is split into two steps: light absorption and G-protein activation. Photoisomerases, on the other hand, are not coupled to G-proteins - they are thought to generate and supply the chromophore that is used by visual opsins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVS-CLRNGWVWDTVGC 114
Cdd:pfam00001   2 NLLVILVILRNKKLRTPTNIFLLNLAVADLLFSLLTLPFWLVYyLNHGDWPFGSALC 58

non-visual pinopsins, member of the class A family of seven-transmembrane G protein-coupled receptors; Pinopsins are found in the pineal organ of birds, reptiles and amphibians, but are absent from teleosts and mammals. 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. They are thought to be involved in light-dependent physiological functions such as photo-entrainment of circadian rhythm, photoperiodicity and body color change. Pinopsins belong the class A of the G protein-coupled receptors and possess seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVV 127
Cdd:cd15084    28 NGLVIVVSIKYKKLRSPLNYILVNLAVADLLVTLFGSSVSFSNNIVGFFVFGKTMCEFEGFMVSLTGIV 96

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd14993    18 NSLVIAVVLRNKHMRTVTNYFLVNLAVADLLVSLFCMPLTLLENVYRPWVFGEVLC 73

neuropeptide Y receptors and related proteins, 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 Gi or Go 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. Also included in this subgroup is prolactin-releasing peptide (PrRP) receptor (previously known as GPR10), which is activated by its endogenous ligand PrRP, a neuropeptide possessing C-terminal Arg-Phe-amide motif. There are two active isoforms of PrRP in mammals: one consists of 20 amino acid residues (PrRP-20) and the other consists of 31 amino acid residues (PrRP-31). PrRP receptor shows significant sequence homology to the NPY receptors, and a micromolar level 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWV 108
Cdd:cd15203    18 NLLVIYVVLRNKSMQTVTNIFILNLAVSDLLLCLVSLPFTLIYTLTKNWP 67

short wave-sensitive 2 opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes Short Wave-Sensitive opsin 2 (SWS2), which mediates visual transduction in response to light at short wavelengths (violet to blue). Vertebrate cone opsins are expressed in cone photoreceptor cells of the retina and involved in mediating photopic vision, which allows color perception. The cone opsins can be classified into four classes according to their peak absorption wavelengths: SWS1 (ultraviolet sensitive), SWS2 (short wave-sensitive), MWS/LWS (medium/long wave-sensitive), and RH2 (medium wave-sensitive, rhodopsin-like opsins). Members of this group belong to the class A of the G protein-coupled receptors and possess seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVVT 128
Cdd:cd15077    18 NVLTIICTIKYKKLRSHLNYILVNLAVANLIVVCFGSTTAFYSFSQMYFVLGPLACKIEGFTATLGGMVS 87

neuropeptide Y receptor type 1, 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. When NPY signals through NPY2R in concert with NPY5R, it induces angiogenesis and consequently plays an important role in revascularization and wound healing. On the other hand, when NPY acts through NPY1R and NPYR5, it acts as a vascular mitogen, leading to restenosis and atherosclerosis.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15395    18 NLALIIIILKQKEMHNVTNILIVNLSFSDLLMTIMCLPFTFVYTLMDHWVFGEAMC 73

medium wave-sensitive opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes Medium Wave-Sensitive opsin, which mediates visual transduction in response to light at medium wavelengths (green). Vertebrate cone opsins are expressed in cone photoreceptor cells of the retina and involved in mediating photopic vision, which allows color perception. The cone opsins can be classified into four classes according to their peak absorption wavelengths: SWS1 (ultraviolet sensitive), SWS2 (short wave-sensitive), MWS/LWS (medium/long wave-sensitive), and RH2 (medium wave-sensitive, rhodopsin-like opsins). Members of this group belong to the class A of the G protein-coupled receptors and possess seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSL 123
Cdd:cd15080    18 NFLTLYVTVQHKKLRTPLNYILLNLAVADLFMVFGGFTTTMYTSMHGYFVFGPTGCNLEGFFATL 82

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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGFSGSLFAVV 127
Cdd:cd15075    18 NATVIIVTLRHKQLRQPLNYALVNLAVADLGTTVFGGLLSVVTNAVGYFNLGRVGCVLEGFAVAFFGIA 86

G protein-coupled receptor 83, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR83, also known as GPR72, is widely expressed in the brain, including hypothalamic nuclei which is involved in regulating energy balance and food intake. The hypothalamic expression of GPR83 is tightly regulated in response to nutrient availability and is decreased in obese mice. A recent study suggests that GPR83 has a critical role in the regulation of systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. GPR83 shares a significant amino acid sequence identity with the tachykinin receptors, however its endogenous ligand is unknown.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15389    18 NSLVCHVIFKNKRMHTATNLFIVNLAVSDILITLLNTPFTLVRFVNSTWVFGKIMC 73

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
                  ....*....|....*....|....*....|....*
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLF 93
Cdd:cd14997    18 NVLVGIVVWKNKDMRTPTNIFLVNLSVADLLVLLV 52

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 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15210    18 NLLTVLALLRSKKLRTRTNAFIINLSISDLLFCAFNLPLAASTFLHQAWIHGETLC 73

retinal G protein coupled receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; This group represents the retinal G-protein coupled receptor (RGR) found exclusively in retinal pigment epithelium (RPE) and Muller cells. RGR is a member of the class A rhodopsin-like receptor family. As with other opsins, RGR binds all-trans retinal and contains a conserved lysine reside on the seventh helix. RGR functions as a photoisomerase to catalyze the conversion of all-trans-retinal to 11-cis-retinal. Two mutations in RGR gene are found in patients with retinitis pigmentosa, indicating that RGR is essential to the visual process.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNgWVWDTVGCVWDGFSGSLFA 125
Cdd:cd15072    18 NGLTILSFCKTRELRTPSNLLVLSLAVADMGISLNALVAASSSLLRR-WPYGSEGCQAHGFQGFFTA 83

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 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15329    18 NALVIIAVCLVKKLRTPSNYLIVSLAVSDLLVALLVMPLAIIYELSGYWPFGEILC 73

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        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGF------SGSLFAV----VT 128
Cdd:cd15402    18 NLLVILSVYRNKKLRNAGNIFVVSLAVADLVVAIYPYPLVLTSIFHNGWNLGYLHCQISGFlmglsvIGSIFNItgiaIN 97

                  ....
gi 1831772131 129 RRCY 132
Cdd:cd15402    98 RYCY 101

orphan G protein-coupled receptor 161, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR161, an orphan GPCR, is a negative regulator of Sonic hedgehog (Shh) signaling, which promotes the processing of zinc finger protein GLI3 into its transcriptional repressor form (GLI3R) during neural tube development. In the absence of Shh, this proteolytic processing is normally mediated by cAMP-dependent protein kinase A (PKA). GPR161 is recruited to primary cilia by a mechanism depends on TULP3 (tubby-related protein 3) and the intraflagellar complex A (IFT-A). Moreover, Gpr161 knockout mice show phenotypes observed in Tulp3/IFT-A mutants, and cause increased Shh signaling in the neural tube. Taken together, GPR161 negatively regulates the PKA-dependent GLI3 processing in the absence of Shh signal by coupling to G(s) protein, which causes activation of adenylate cyclase, elevated cAMP levels, and activation of PKA. Conversely, in the presence of Shh, GPR161 is removed from the cilia by internalization into the endosomal recycling compartment, leading to downregulation of its activity and thereby allowing Shh signaling to proceed. In addition, GPR161 is over-expressed in triple-negative breast cancer (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression) and correlates with poor prognosis. Mutations of GPR161 have also been implicated as a novel cause for pituitary stalk interruption syndrome (PSIS), a rare congenital disease of the pituitary gland. GPR161 is a member of the class A family of GPCRs, which contains 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        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWdtvGCVWDGFSGSLFAVVT 128
Cdd:cd15214    17 NLVIVVTLYKKSYLLTLSNKFVFSLTLSNLLLSVLVLPFVVTSSIRREWIF---GVVWCNFSALLYLLIS 83

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15206    18 NILVIVTLVQNKRMRTVTNVFLLNLAVSDLLLAVFCMPFTLVGQLLRNFIFGEVMC 73

trissin receptor and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup represents the Drosophila melanogaster trissin receptor and closely related invertebrate proteins which are a member of the class A family of seven-transmembrane G-protein coupled receptors. The cysteine-rich trissin has been shown to be an endogenous ligand for the orphan CG34381 in Drosophila melanogaster. Trissin is a peptide composed of 28 amino acids with three intrachain disulfide bonds with no significant structural similarities to known endogenous peptides. Cysteine-rich peptides are known to have antimicrobial or toxicant activities, although frequently their mechanism of action is poorly understood. Since the expression of trissin and its receptor is reported to predominantly localize to the brain and thoracicoabdominal ganglion, trissin is predicted to behave as a neuropeptide. 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 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15012    17 NLLVILVVTSHRRMRTITNFFLANLAVADLCVGIFCVLQNLSIYLIPSWPFGEVLC 72

substance-K receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The substance-K receptor (SKR), also known as tachykinin receptor 2 (TACR2) or neurokinin A receptor or NK2R, is a G-protein coupled receptor that specifically binds to neurokinin A. 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 the regulation of gastrointestinal motility, secretion, vascular permeability, and pain perception.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGF 119
Cdd:cd16004    18 NATVIWIILAHRRMRTVTNYFIVNLALADLSMAAFNTAFNFVYASHNDWYFGLEFCRFQNF 78

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGF------SGSLFAV----VT 128
Cdd:cd15209    18 NLLVILSVLRNKKLRNAGNIFVVSLSVADLVVAIYPYPLILHAIFHNGWTLGQLHCQASGFimglsvIGSIFNItaiaIN 97

                  ....
gi 1831772131 129 RRCY 132
Cdd:cd15209    98 RYCY 101

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGCVWDGF 119
Cdd:cd15000    17 NFVLLYILASNRSLRTPTNLLIGNMALADLLTLLVCPWMFLVHDFFQNYVLGSVGCKLEGF 77

adenosine receptor subfamily, member of the class A family of seven-transmembrane G protein-coupled receptors; The adenosine receptors (or P1 receptors), a family of G protein-coupled purinergic receptors, bind adenosine as their endogenous ligand. There are four types of adenosine receptors in human, designated as A1, A2A, A2B, and A3. Each type is encoded by a different gene and has distinct functions with some overlap. For example, both A1 and A2A receptors are involved in regulating myocardial oxygen consumption and coronary blood flow in the heart, while the A2A receptor also has a broad spectrum of anti-inflammatory effects in the body. These two receptors also expressed in the brain, where they have important roles in the release of other neurotransmitters such as dopamine and glutamate, while the A2B and A3 receptors found primarily in the periphery and play important roles in inflammation and immune responses. The A1 and A3 receptors preferentially interact with G proteins of the G(i/o) family, thereby lowering the intracellular cAMP levels, whereas the A2A and A2B receptors interact with G proteins of the G(s) family, activating adenylate cyclase to elevate cAMP levels.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVS 101
Cdd:cd14968    18 NVLVIWAVKLNRALRTVTNYFIVSLAVADILVGALAIPLAILI 60

serotonin receptor subtypes B1 and B2 from Aplysia californica and similar proteins; member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes Aplysia californica serotonin receptors Ap5-HTB1 and Ap5-HTB2, and similar proteins from bilateria including insects, mollusks, annelids, and worms. Ap5-HTB1 is one of the several different receptors for 5-hydroxytryptamine (5HT, serotonin). In Aplysia, serotonin plays important roles in a variety of behavioral and physiological processes mediated by the central nervous system. These include circadian clock, feeding, locomotor movement, cognition and memory, synaptic growth and synaptic plasticity. Both Ap5-HTB1 and Ap5-HTB2 receptors are coupled to G-proteins that stimulate phospholipase C, leading to the activation of phosphoinositide metabolism. Ap5-HTB1 is expressed in the reproductive system, whereas Ap5-HTB2 is expressed in the central nervous system.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC-VWDGF 119
Cdd:cd15065    17 NVLVCLAIFTDRRLRKKSNLFIVSLAVADLLVALLVMTFAVVNDLLGYWLFGETFCnIWISF 78

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVWDTVGC 114
Cdd:cd15979    18 NMLIIVVLGLNKRLRTVTNSFLLSLALSDLMLAVFCMPFTLIPNLMGTFIFGEVIC 73

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
                  ....*....|....*....|....*....|....*....
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTF 97
Cdd:cd15204    18 NLLLIAVLARYKKLRTLTNLLIANLALSDFLVAVFCLPF 56

neuromedin U receptor subtype 2, 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        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831772131  59 NLLVLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRN-GWVWDTVGCVwdgFSGSLFAVV 127
Cdd:cd15357    18 NLLVCLVILKHQNMKTPTNYYLFSLAVSDLLVLLFGMPLEVYEMWSNyPFLFGPVGCY---FKTALFETV 84