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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   1 VAAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15076 196 VAAQQQESASTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYMVNNRDHGLDLRLVTIPAFFSKSSCVYNPIIYCFMNKQ 275

short wave-sensitive 1 opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes Short Wave-Sensitive opsin 1 (SWS1), which mediates visual transduction in response to light at short wavelengths (ultraviolet 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   1 VAAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15076 196 VAAQQQESASTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYMVNNRDHGLDLRLVTIPAFFSKSSCVYNPIIYCFMNKQ 275

G protein-coupled chemokine receptor-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 77025110   13 KAEREVSRMVVVMVGSFCLCYVPYA----ALAMYIVNNRNHGLDLRLVTIPAF----FSKSACVYNPIIYCFMNK 79
Cdd:PHA03087 237 KKNKKAIKLVLIIVILFVIFWLPFNvsvfVYSLHILHFKSGCKAVKYIQYALHvteiISLSHCCINPLIYAFVSE 311

short wave-sensitive 1 opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes Short Wave-Sensitive opsin 1 (SWS1), which mediates visual transduction in response to light at short wavelengths (ultraviolet 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   1 VAAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15076 196 VAAQQQESASTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYMVNNRDHGLDLRLVTIPAFFSKSSCVYNPIIYCFMNKQ 275

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 77025110   2 AAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15080 197 AAQQQESATTQKAEKEVTRMVIIMVIAFLICWVPYASVAFYIFTHQGSDFGPIFMTIPAFFAKSSAVYNPVIYILMNKQ 275

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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 77025110   4 QQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd14969 203 NSAITKRTKKAEKKVAKMVLVMIVAFLIAWTPYAVVSLYVSFGGESTIPPLLATIPALFAKSSTIYNPIIYVFMNKQ 279

non-visual VA (vertebrate ancient) opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; The vertebrate ancient (VA) opsin photopigments were originally identified in salmon and they appear to have diverged early in the evolution of vertebrate opsins. VA opsins are localized in the inner retina and the brain in teleosts. The vertebrate non-visual opsin family includes pinopsins, parapinopsin, VA (vertebrate ancient) opsins, and parietopsins. These non-visual opsins are expressed in various extraretinal 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. The VA 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   1 VAAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15082 207 VSNTQGRLGNARKPERQVTRMVVVMIVAFMVCWTPYAAFSILVTAHPTIHLDPRLAAIPAFFSKTAAVYNPIIYVFMNKQ 286

non-visual parietopsins, member of the class A family of seven-transmembrane G protein-coupled receptors; Parietopsin is a non-visual green light-sensitive opsin that was initially identified in the parietal eye of lizards. 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. Parietopsin 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 77025110   4 QQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15085 199 EQQGGKNCPEEEERAVIMVLAMVIAFLICWLPYTVFALIVVVNPELSISPLAATMPTYFAKTSPVYNPIIYIFLNKQ 275

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 77025110   4 QQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMNKQ 80
Cdd:cd15078 198 QTFQVIKILKYEKKVAKMCLLMISTFLICWMPYAVVSLLVTSGYSKLVTPTIAIIPSLFAKSSTAYNPVIYIFMIRK 274

vertebrate melanopsins and related opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group represent the Gq-coupled rhodopsin subfamily consists of melanopsins, insect photoreceptors R1-R6, invertebrate Gq opsins as well as their closely related opsins. Melanopsins (also called Opsin-4) are the primary photoreceptor molecules for non-visual functions such as the photo-entrainment of the circadian rhythm and pupillary constriction in mammals. Mammalian melanopsins are expressed only in the inner retina, whereas non-mammalian vertebrate melanopsins are localized in various extra-retinal tissues such as iris, brain, pineal gland, and skin. The outer photoreceptors (R1-R6) are the insect Drosophila equivalent to the vertebrate rods and are responsible for image formation and motion detection. The invertebrate G(q) opsins includes the arthropod and mollusk visual opsins as well as invertebrate melanopsins, which are also found in vertebrates. Arthropods possess color vision by the use of multiple opsins sensitive to different light wavelengths. Members of this subfamily belong to the class A of the G protein-coupled receptors and have seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 77025110  11 TQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCF 76
Cdd:cd15083 217 RRQAEVKTAKIALLLVLLFCLAWTPYAVVALIGQFGYLEVLTPLATAIPAAFAKTSAIYNPVIYAF 282

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 77025110  13 KAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMN 78
Cdd:cd15337 220 KAEIRIAKVAIILISLFLLSWTPYAVVALLGQFGPAYWITPYVSELPVMFAKASAIYNPIIYALSH 285

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        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 77025110     3 AQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPA---FFSKSACVYNPIIY 74
Cdd:pfam00001 182 ASKQKSSERTQRRRKALKTLAVVVVVFILCWLPYHIVNLLDSLALDCELSRLLDKALSvtlWLAYVNSCLNPIIY 256

insect photoreceptors R1-R6 and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the insect photoreceptors and their closely related proteins. The Drosophila eye is composed of about 800 unit eyes called ommatidia, each of which contains eight photoreceptor cells (R1-R8). The six outer photoreceptors (R1-R6) function like the vertebrate rods and are responsible for motion detection in dim light and image formation. The R1-R6 photoreceptors express a blue-absorbing pigment, Rhodopsin 1(Rh1). The inner photoreceptors (R7 and R8) are considered the equivalent of the color-sensitive vertebrate cone cells, which express a range of different pigments. The R7 photoreceptors express one of two different UV absorbing pigments, either Rh3 or Rh4. Likewise, the R8 photoreceptors express either the blue absorbing pigment Rh5 or green absorbing pigment Rh6. These photoreceptors 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 77025110  12 QKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIY 74
Cdd:cd15079 219 QSAEIRIAKVALTNVFLWFIAWTPYAVVALIGAFGNQSLLTPLVSMIPALFAKTAACYNPIVY 281

neuromedin-K receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The neuromedin-K receptor (NKR), also known as tachykinin receptor 3 (TACR3) or neurokinin B receptor or NK3R, is a G-protein coupled receptor that specifically binds to neurokinin B. The tachykinins (TKs) 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. NK3R is activated by its high-affinity ligand, NKB, which is primarily involved in the central nervous system and plays a critical role in the regulation of gonadotropin hormone release and the onset of puberty.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 77025110  13 KAEREVSRMVVVMVGSFCLCYVPYAALamYIVNNRNHGLD----LRLVTIPAFF-SKSACVYNPIIYCFMNKQ 80
Cdd:cd16003 207 RAKRKVVKMMIIVVLTFAICWLPYHIY--FIVTGLYQQLNrwkyIQQVYLASFWlAMSSTMYNPIIYCCLNKR 277

vasopressin receptors and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Members of this group form a subfamily within the class A G-protein coupled receptors (GPCRs), which includes the vasopressin and oxytocin receptors, the gonadotropin-releasing hormone receptors (GnRHRs), the neuropeptide S receptor (NPSR), and orphan GPR150. These receptors share significant sequence homology with each other, suggesting that they have a common evolutionary origin. Vasopressin, also known as arginine vasopressin or anti-diuretic hormone, is a neuropeptide synthesized in the hypothalamus. The actions of vasopressin are mediated by the interaction of this hormone with three tissue-specific subtypes: V1AR, V1BR, and V2R. Although vasopressin differs from oxytocin by only two amino acids, they have divergent physiological functions. Vasopressin is involved in regulating osmotic and cardiovascular homeostasis, whereas oxytocin plays an important role in the uterus during childbirth and in lactation. 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. Neuropeptide S (NPS) promotes arousal and anxiolytic-like effects by activating its cognate receptor NPSR. NPSR has also been associated with asthma and allergy. GPR150 is an orphan receptor closely related to the oxytocin and vasopressin receptors.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 77025110   1 VAAQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIYCFMN 78
Cdd:cd14986 211 VSCVSSRVSLISRAKIKTIKMTLVIILAFILCWTPYFIVQLLDVYAGMQQLENDAYVVSETLASLNSALNPLIYGFFS 288

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 77025110  13 KAEREVSRMVVVMVGSFCLCYVPyaalaMYIVN-----------NRNHGLDLRLVTIPAFFSksACVyNPIIYCFMNK 79
Cdd:cd15206 194 EAKKRVIRMLFVIVVEFFICWTP-----LYVINtwkafdppsaaRYVSSTTISLIQLLAYIS--SCV-NPITYCFMNK 263

tachykinin receptors and related receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the neurokinin/tachykinin receptors and its closely related receptors such as orphan GPR83 and leucokinin-like peptide receptor. The tachykinins are widely distributed throughout the mammalian central and peripheral nervous systems and act as excitatory transmitters on neurons and cells in the gastrointestinal tract. The TKs are characterized by a common five-amino acid C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is a hydrophobic residue. The three major mammalian tachykinins are substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). The physiological actions of tachykinins are mediated through three types of receptors: neurokinin receptor type 1 (NK1R), NK2R, and NK3R. SP is a high-affinity endogenous ligand for NK1R, which interacts with the Gq protein and activates phospholipase C, leading to elevation of intracellular calcium. NK2R is a high-affinity receptor for NKA, the tachykinin neuropeptide substance K. SP and NKA are found in the enteric nervous system and mediate in the regulation of gastrointestinal motility, secretion, vascular permeability, and pain perception. NK3R is activated by its high-affinity ligand, NKB, which is primarily involved in the central nervous system and plays a critical role in the regulation of gonadotropin hormone release and the onset of puberty.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 77025110   3 AQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAF--FSKSACVYNPIIYCFMN 78
Cdd:cd15202 204 ATTERYFALRRKKKKVIKMLMVVVVLFALCWLPFNIYVLLLSSKPDYLIKTINAVYFAFhwLAMSSTCYNPFIYCWLN 281

vertebrate melanopsins (Opsin-4), member of the class A family of seven-transmembrane G protein-coupled receptors; Melanopsin (also called Opsin-4) is the G protein-coupled photopigment that mediates non-visual responses to light. In mammals, these photoresponses include the photo-entrainment of circadian rhythm, pupillary constriction, and acute nocturnal melatonin suppression. Mammalian melanopsins are expressed only in the inner retina, whereas non-mammalian vertebrate melanopsins are localized in various extra-retinal tissues such as iris, brain, pineal gland, and skin. Melanopsins 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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 77025110   2 AAQQQESattQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVYNPIIY 74
Cdd:cd15336 210 KAKQYQR---MKNEWKMAKIAFVVILLFVLSWSPYACVALIAWAGYAHLLTPYMKSVPAVIAKASAIYNPIIY 279

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 77025110   8 SATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNH----GLDLRLVTIPAFFSKSACvyNPIIYCFMNKQ 80
Cdd:cd14971 202 SEGSRRAKRKVTRLVLVVVVLFAACWGPIHAILLLVALGPFPltyaTYALRIWAHCLAYSNSAV--NPVLYAFLSEH 276

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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   2 AAQQQESATTQKaeREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSK----SACVYNPIIYCFM 77
Cdd:cd15203 208 SSRRRRSELRRK--RRTNRLLIAMVVVFAVCWLPLNLFNLLRDFEPLPQIDGRHFYLIFLICHliamSSACVNPLLYGWL 285

                ...
gi 77025110  78 NKQ 80
Cdd:cd15203 286 NDN 288

allatostatin-A receptor in insects, member of the class A family of seven-transmembrane G protein-coupled receptors; The G protein-coupled AstA receptor binds allatostatin A. Three distinct types of allatostatin have been identified in the insects and crustaceans: AstA, AstB, and AstC. They both inhibit the biosynthesis of juvenile hormone and exert an inhibitory influence on food intake. Therefore, allatostatins are considered as potential targets for insect control.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 77025110   8 SATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAF----FSKSaCVyNPIIYCFM 77
Cdd:cd15096 205 SAESQRGKRRVTRLVVVVVVVFAICWLPIHIILLLKYYGVLPETVLYVVIQILSnclaYGNS-CV-NPILYAFL 276

orexin receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; 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. Thus, activation of OX1R or OX2R will activate phospholipase activity and the phosphatidylinositol and calcium signaling pathways. Additionally, OX2R activation can also lead to inhibition of adenylate cyclase.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 77025110  13 KAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSACVY----NPIIYCFM 77
Cdd:cd15208 227 RSRRKTAKMLIVVVIMFAICYLPVHLLNILRYVFGLFTVDRETIYAWFLFSHWLVYAnsaiNPIIYNFM 295

G protein-coupled chemokine receptor-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 77025110   13 KAEREVSRMVVVMVGSFCLCYVPYA----ALAMYIVNNRNHGLDLRLVTIPAF----FSKSACVYNPIIYCFMNK 79
Cdd:PHA03087 237 KKNKKAIKLVLIIVILFVIFWLPFNvsvfVYSLHILHFKSGCKAVKYIQYALHvteiISLSHCCINPLIYAFVSE 311

proton-sensing G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Proton/pH-sensing G-protein coupled receptors sense pH of 7.6 to 6.0. They mediate a variety of biological activities in neutral and mildly acidic pH conditions, whereas the acid-sensing ionotropic ion channels typically sense strong acidic pH. The proton/pH-sensing receptor family includes the G2 accumulation receptor (G2A, also known as GPR132), the T cell death associated gene-8 (TDAG8, GPR65) receptor, ovarian cancer G-protein receptor 1 (OGR-1, GPR68), and G-protein-coupled receptor 4 (GPR4).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   8 SATTQKAE-REVSRMVVVMVGSFCLCYVPYAAL-----AMYIVNNRNHGLDLRLVT---IPAFFSKSACVYNPIIYCFMN 78
Cdd:cd15160 194 SPSLEREEkRKIIGLLLSIVVIFLLCFLPYHVVllvrsVIELVQNGLCGFEKRVFTayqISLCLTSLNCVADPILYIFVT 273

                .
gi 77025110  79 K 79
Cdd:cd15160 274 E 274

purinoceptor and its related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; Members of this subfamily include lysophosphatidic acid receptor, P2 purinoceptor, protease-activated receptor, platelet-activating factor receptor, Epstein-Barr virus induced gene 2, proton-sensing G protein-coupled receptors, GPR35, and GPR55, among others. 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   3 AQQQESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIPAFFSKSA--------CVYNPIIY 74
Cdd:cd14982 193 RRRSKQSQKSVRKRKALRMILIVLAVFLVCFLPYHVTRILYLLVRLSFIADCSARNSLYKAYRItlclaslnSCLDPLIY 272

                ....*
gi 77025110  75 CFMNK 79
Cdd:cd14982 273 YFLSK 277

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 77025110   8 SATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMY--IVNNRNHGLDLRLVTIPAFFSKSACVYNPIIY-CFM 77
Cdd:cd15195 214 TNSLERARMRTLRMTALIVLTFIVCWGPYYVLGLWywFDKESIKNLPPALSHIMFLLGYLNPCLHPIIYgVFM 286

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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 77025110   9 ATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIV------NNRNHGLDLRLVTIPAFFSKSACvyNPIIYCFMNK 79
Cdd:cd15012 197 SSSIEARRKVVRLLVAVVVSFALCNLPYHARKMWQYwsepyrCDSNWNALLTPLTFLVLYFNSAV--NPLLYAFLSK 271

somatostatin receptor type 5, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs) are composed of five distinct subtypes (SSTR1-5) that display strong sequence similarity with opioid receptors. All five receptor subtypes bind the natural somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. SSTR5 is coupled to inward rectifying K channels and phospholipase C, and plays critical roles in growth hormone and insulin secretion. SSTR5 acts as a negative regulator of PDX-1 (pancreatic and duodenal homeobox-1) expression, which is a conserved homeodomain-containing beta cell-specific transcription factor essentially involved in pancreatic development, among many other functions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   8 SATTQKAEREVSRMVVVMVGSFCLCYVPYaalamYIVNNRNhgLDLRLVTIPAF---------FSKSACVYNPIIYCFMN 78
Cdd:cd15974 198 STKRRKSERKVTRMVVIIVVVFVFCWLPF-----YMLNIVN--LIVILPEEPAFvgvyffvvvLSYANSCANPILYGFLS 270

somatostatin-like receptor for allatostatin C, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs) are composed of five distinct subtypes (SSTR1-5) that display strong sequence similarity with opioid receptors. All five receptor subtypes bind the natural somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. In Drosophila melanogaster and other insects, a 15-amino-acid peptide named allatostatin C(AstC) binds the somatostatin-like receptors. Two AstC receptors have been identified in Drosophila with strong sequence homology to human somatostatin and opioid receptors.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 77025110   7 ESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYIVNNRNhGLDLRLVTIPAFFSKSACVY-----NPIIYCFMN 78
Cdd:cd15094 200 KSKEKRRSHRKVTRLVLTVISVYIICWLPYWAFQVHLIFLPP-GTDMPKWEILMFLLLTVLSYansmvNPLLYAFLS 275

proton-sensing G protein-coupled receptor 4, member of the class A family of seven-transmembrane G protein-coupled receptors; G-protein-coupled receptor 4 (GPR4) is a member of the proton-sensing G-protein-coupled receptor (GPCR) family which also includes the G2 accumulation receptor (G2A, also known as GPR132), the T cell death associated gene-8 receptor (TDAG8, GPR65), ovarian cancer G-protein receptor 1 (OGR-1, GPR68), and G-protein-coupled receptor 4 (GPR4). Proton-sensing G-protein coupled receptors sense pH of 7.6 to 6.0 and mediates a variety of biological activities in neutral and mildly acidic pH conditions, whereas the acid-sensing ionotropic ion channels typically sense strong acidic pH. GPR4 overexpression in melanoma cells was shown to reduce cell migration, membrane ruffling, and cell spreading under acidic pH conditions. Activation of GPR4 via extracellular acidosis is coupled to the G(s), G(q), and G(12/13) pathways.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   9 ATTQKAEREVSRMVVVMVGSFCLCYVPYAAL-----AMYIVNNRNHGLDLRLvtIPAFFSKSA-----CVYNPIIYCFMN 78
Cdd:cd15366 196 STEQQEKAKIKRLALSLIAIVLLCFAPYHVLllsrsVVYLGKPCDCGFEERV--FTAYHVSLAltslnCVADPILYCLVN 273

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 77025110   7 ESATTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYI----VNNRNHGLDLRL----VTIPAFFSkSACvyNPIIYCFMN 78
Cdd:cd15205 215 EMSKISRKKKRAVKMMVTVVLLFAVCWAPFHVVHMMIeysnLENKYDGVTIKLifaiVQLIGFSN-SFN--NPIVYAFMN 291

galanin receptor subtypes 2 and 3, 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
                ....*....|....*....|....*....|.
gi 77025110  11 TQKAEREVSRMVVVMVGSFCLCYVPYAALAM 41
Cdd:cd15097 203 SKRAKRKVTKMIIIVTALFCLCWLPHHVVIL 233

anaphylatoxin receptors and related G protein-coupled chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily of G-protein coupled receptors includes anaphylatoxin receptors, formyl peptide receptors (FPR), prostaglandin D2 receptor 2, GPR1, and related chemokine receptors. The anaphylatoxin receptors are a group of G-protein coupled receptors that bind anaphylatoxins. The members of this group include C3a and C5a receptors. The formyl peptide receptors (FPRs) are chemoattractant GPCRs that involved in mediating immune responses to infection. They are expressed mainly on polymorphonuclear and mononuclear phagocytes and bind N-formyl-methionyl peptides (FMLP), which are derived from the mitochondrial proteins of ruptured host cells or invading pathogens. Chemokine receptor-like 1 (also known as chemerin receptor 23) is a GPCR for the chemoattractant adipokine chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with chemerin induces activation of the MAPK and PI3K signaling pathways leading to downstream functional effects, such as a decrease in immune responses, stimulation of adipogenesis, and angiogenesis. On the other hand, resolvin E1 negatively regulates the cytokine production in macrophages by reducing the activation of MAPK1/3 and NF-kB pathways. Prostaglandin D2 receptor, also known as CRTH2, is a chemoattractant G-protein coupled receptor expressed on T helper type 2 cells that binds prostaglandin D2 (PGD2). PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses and also causes vasodilation. PGD2 exerts its inflammatory effects by binding to two G-protein coupled receptors, the D-type prostanoid receptor (DP) and PD2R2 (CRTH2). PD2R2 couples to the G protein G(i/o) type which leads to a reduction in intracellular cAMP levels and an increase in intracellular calcium. GPR1 is an orphan receptor that can be activated by the leukocyte chemoattractant chemerin, thereby suggesting that some of the anti-inflammatory actions of chemerin may be mediated through GPR1.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 77025110  20 RMVVVMVGSFCLCYVPYAALAMYIVNNRNHGLDLRLVTIP-----AFFskSACVyNPIIYCFMNKQ 80
Cdd:cd14974 207 RVLLAVVVAFFLCWLPYHVFALLELVAAAGLPEVVLLGLPlatglAYF--NSCL-NPILYVFMGQD 269