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 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15081  208 VAQQQKESESTQKAEKEVSRMVVVMIFAYCFCWGPYTFFACFAAANPGYAFHPLAAALPAYFAKSATIYNPIIYVFMNRQ 287

long wave-sensitive opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; Long Wave-Sensitive opsin is also called red-sensitive opsin or red cone photoreceptor pigment, which mediates visual transduction in response to light at long wavelengths. 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 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15081  208 VAQQQKESESTQKAEKEVSRMVVVMIFAYCFCWGPYTFFACFAAANPGYAFHPLAAALPAYFAKSATIYNPIIYVFMNRQ 287

long wave-sensitive opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; Long Wave-Sensitive opsin is also called red-sensitive opsin or red cone photoreceptor pigment, which mediates visual transduction in response to light at long wavelengths. 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 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15081  208 VAQQQKESESTQKAEKEVSRMVVVMIFAYCFCWGPYTFFACFAAANPGYAFHPLAAALPAYFAKSATIYNPIIYVFMNRQ 287

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15077  196 VAKQQEQSASTQKAEREVTKMVVVMVLGFLVCWLPYASFALWVVTNRGEPFDLRLASIPSVFSKASTVYNPVIYVFMNKQ 275

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 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15082  207 VSNTQGRLGNARKPERQVTRMVVVMIVAFMVCWTPYAAFSILVTAHPTIHLDPRLAAIPAFFSKTAAVYNPIIYVFMNKQ 286

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 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15076  196 VAAQQQESASTQKAEREVSRMVVVMVGSFCLCYVPYAALAMYMVNNRDHGLDLRLVTIPAFFSKSSCVYNPIIYCFMNKQ 275

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 208972198   4 QQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15085  199 EQQGGKNCPEEEERAVIMVLAMVIAFLICWLPYTVFALIVVVNPELSISPLAATMPTYFAKTSPVYNPIIYIFLNKQ 275

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 208972198   2 AKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNR 79
Cdd:cd15337  209 GKDTEKNDARKKAEIRIAKVAIILISLFLLSWTPYAVVALLGQFGPAYWITPYVSELPVMFAKASAIYNPIIYALSHP 286

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 208972198  12 QKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNRQ 80
Cdd:cd15074  211 HKIERKVTKVAVLICAGFLIAWTPYAVVSMWSAFGSPDSVPILASILPALFAKSSCMYNPIIYLLFSSK 279

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 208972198   9 ESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVF 76
Cdd:cd15083  215 KARRQAEVKTAKIALLLVLLFCLAWTPYAVVALIGQFGYLEVLTPLATAIPAAFAKTSAIYNPVIYAF 282

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198  13 KAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLM--AALPAYF-AKSATIYNPIIYVFMNR 79
Cdd:cd15390  214 RAKRKVVKMMIVVVVIFAICWLPYHLYFILTYLYPDINSWKYIqqIYLAIYWlAMSNSMYNPIIYCWMNK 283

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 208972198    1 VAKQQKESESTQKAEKeVTRMVVVMIMAYCVCWGPY*FFACFAAAHPG---YAFHPLMAALPAYFAKSATIYNPIIY 74
Cdd:pfam00001 181 SASKQKSSERTQRRRK-ALKTLAVVVVVFILCWLPYHIVNLLDSLALDcelSRLLDKALSVTLWLAYVNSCLNPIIY 256

KiSS1-derived peptide (kisspeptin) receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The G protein-coupled KiSS1-derived peptide receptor (GPR54 or kisspeptin receptor) binds the peptide hormone kisspeptin (previously known as metastin), which encoded by the metastasis suppressor gene (KISS1) expressed in various endocrine and reproductive tissues. The KiSS1 receptor is coupled to G proteins of the G(q/11) family, which lead to activation of phospholipase C and increase of intracellular calcium. This signaling cascade plays an important role in reproduction by regulating the secretion of gonadotropin-releasing hormone.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 208972198   4 QQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPL-----MAALPAYFAKSATiyNPIIYVFM 77
Cdd:cd15095  204 SEQLSERALRQKRKVTRMVIVVVVLFAICWLPNHVLNLWQRFDPNFPETYAtyalkIAALCLSYANSAV--NPFVYAFM 280

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 208972198  14 AEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAAlPAYF----AKSATIYNPIIYVFMNRQ 80
Cdd:cd15979  201 AKKRVIRMLVVIVAMFFLCWLPIFSANTWRAFDPLSAHRALSGA-PISFihllSYTSACVNPLVYCFMNRR 270

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   4 QQKESESTQ-KAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPgyAFHPLMAALPAYF-----AKSATIYNPIIYVFM 77
Cdd:cd14992  206 SIKEVERKRlKCKRRVIKMLVCVVVLFVICWLPFHLFFLLRDFFP--LIMKEKHTLQVYYflhwiAMSNSMYNPIIYVTL 283

                 ..
gi 208972198  78 NR 79
Cdd:cd14992  284 NN 285

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 208972198  12 QKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIY 74
Cdd:cd15079  219 QSAEIRIAKVALTNVFLWFIAWTPYAVVALIGAFGNQSLLTPLVSMIPALFAKTAACYNPIVY 281

neurokinin 1 receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1) or substance P receptor (SPR), is a G-protein coupled receptor found in the mammalian central nervous and peripheral nervous systems. The tachykinins 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. SP is an extremely potent vasodilator through endothelium dependent mechanism and is released from the autonomic sensory nerves. 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 208972198  14 AEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAAL---PAYFAKSATIYNPIIYVFMN 78
Cdd:cd16002  210 AKRKVVKMMIVVVCTFAICWLPYHIYFLLQYFHPELYEQKFIQQVylaIMWLAMSSTMYNPIIYCCLN 277

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   1 VAKQQKESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHP------GYAFHpLMAALPAYfAKSATiyNPIIY 74
Cdd:cd14971  195 VAVRPVLSEGSRRAKRKVTRLVLVVVVLFAACWGPIHAILLLVALGPfpltyaTYALR-IWAHCLAY-SNSAV--NPVLY 270

                 ....*.
gi 208972198  75 VFMNRQ 80
Cdd:cd14971  271 AFLSEH 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 208972198   3 KQQKESESTQKAEKEVTRMVVVMIMAYCVCWGP---------Y*FFACFAAAHPGYAFhpLMAALpayFAKSATIYNPII 73
Cdd:cd15203  207 LSSRRRRSELRRKRRTNRLLIAMVVVFAVCWLPlnlfnllrdFEPLPQIDGRHFYLIF--LICHL---IAMSSACVNPLL 281

                 ....*..
gi 208972198  74 YVFMNRQ 80
Cdd:cd15203  282 YGWLNDN 288

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 208972198  16 KEVTRMVVVMIMAYCVCWGPY*FFACFAAAHP---GYAFHPLMAALPAYFAKSATIYNPIIYVFMN 78
Cdd:cd15397  221 KRINVMLVSLVAAFALCWLPLNVFNAIADWNHeaiPHCQHNLIFSLCHLAAMASTCVNPIIYGFLN 286

prostaglandin D2 receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; 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. PD2R2 is involved in mediating chemotaxis of Th2 cells, eosinophils, and basophils generated during allergic inflammatory processes. CRTH2 (PD2R2), but not DP receptor, undergoes agonist-induced internalization which is one of key processes that regulates the signaling of the GPCR.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 208972198  19 TRMVVVMIMAYCVCWGPY*F-FACFAAAHPGYAFHPLM-AALPayFAKSA----TIYNPIIYVF 76
Cdd:cd15118  214 VRLVVSVVVSFALCWAPYHIfSIIEVMAHNQHSLRPLViQGLP--FATTLaflnSVLNPVLYVF 275

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 208972198  20 RMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALP-----AYFaksATIYNPIIYVFMNRQ 80
Cdd:cd14974  207 RVLLAVVVAFFLCWLPYHVFALLELVAAAGLPEVVLLGLPlatglAYF---NSCLNPILYVFMGQD 269

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 208972198   6 KESESTQKAEKEVTRMVVVMIMAYCVCWGPY*FF--ACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNR 79
Cdd:cd15096  203 RRSAESQRGKRRVTRLVVVVVVVFAICWLPIHIIllLKYYGVLPETVLYVVIQILSNCLAYGNSCVNPILYAFLSQ 278

invertebrate neuropeptide receptor-like, member of the class A family of seven-transmembrane G protein-coupled receptors; This subgroup includes putative neuropeptide receptor found in invertebrates, which is a member of class A of 7-transmembrane G protein-coupled receptors. This orphan receptor shares a significant amino acid sequence identity with the neurokinin 1 receptor (NK1R). The endogenous ligand for NK1R is substance P, an 11-amino acid peptide that functions as a vasodilator and neurotransmitter and is released from the autonomic sensory nerve fibers.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 208972198  13 KAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHP-----LMAALPAYFAKSATIYNPIIYVFMNR 79
Cdd:cd15391  212 KSKRKVIKMLVFVVLMFGICWLPLHLFNLVQDFSTVFRNMPqhttrLIYGACHWIAMSNSFVNPIIYLFMND 283

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

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gi 208972198  12 QKAEKEVTRMVVVMIMAYCVCWGPY 36
Cdd:cd15093  205 KRSERKVTRMVVMVVVVFVICWLPF 229

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   1 VAKQQKESEStQKAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHP----LMAALPAYFAKSATIYNPIIYVF 76
Cdd:cd15094  195 VGPKNKSKEK-RRSHRKVTRLVLTVISVYIICWLPYWAFQVHLIFLPPGTDMPkweiLMFLLLTVLSYANSMVNPLLYAF 273

                 ..
gi 208972198  77 MN 78
Cdd:cd15094  274 LS 275

histamine subtype H2 receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes histamine receptor subtype H2R, a member of histamine receptor family, which belongs to the class A of GPCRs. Histamine plays a key role as chemical mediator and neurotransmitter in various physiological and pathophysiological processes in the central and peripheral nervous system. Histamine exerts its functions by binding to four different G protein-coupled receptors (H1-H4). The H2R subtype selectively interacts with the G(s)-type G protein that activates adenylate cyclase, leading to increased cAMP production and activation of Protein Kinase A. H2R is found in various tissues such as the brain, stomach, and heart. Its most prominent role is in histamine-induced gastric acid secretion. 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   2 AKQQKESESTQ-KAEKEVTRMVVVMIMAYCVCWGPY*F---FACFAAAHPGYAFHPLMAALPayFAKSAtiYNPIIYVFM 77
Cdd:cd15051  204 ASTANSSKSAAtAREHKATVTLAAVLGAFIICWFPYFTyftYRGLCGDNINETALSVVLWLG--YANSA--LNPILYAFL 279

                 ..
gi 208972198  78 NR 79
Cdd:cd15051  280 NR 281

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208972198   4 QQKES-ESTQKAEKEVTRMVVVMIMAYCVCWGPY*ffacfaaahpGYA----FHPLMAALPAY----------FAKSATI 68
Cdd:cd15204  202 QQTEQiRRRLRRRRRKVRLLVVILTAFVLCWAPYY----------GYAivrdFFPTLLSKEKLnttifyiveaLAMSNSM 271

                         90
                 ....*....|
gi 208972198  69 YNPIIYVFMN 78
Cdd:cd15204  272 INTVVYVAFN 281

chemokine-like receptor 1, member of the class A family of seven-transmembrane G protein-coupled receptors; 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. CMKLR1 is prominently expressed in dendritic cells and macrophages.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 208972198  20 RMVVVMIMAYCVCWGPY*FFACFAAAH---PGYAF---HPLMAALpayfAKSATIYNPIIYVFM 77
Cdd:cd15116  217 KIIAAVIVTFFLCWAPYHILNLLEMEAtrsPASVFkigLPITSSL----AFINSCLNPILYVFM 276

super conserved receptor expressed in brain and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; The SREB (super conserved receptor expressed in brain) subfamily consists of at least three members, named SREB1 (GPR27), SREB2 (GPR85), and SREB3 (GPR173). They are very highly conserved G protein-coupled receptors throughout vertebrate evolution, however no endogenous ligands have yet been identified. SREB2 is greatly expressed in brain regions involved in psychiatric disorders and cognition, such as the hippocampal dentate gyrus. Genetic studies in both humans and mice have shown that SREB2 influences brain size and negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent cognitive function, all of which are suggesting a potential link between SREB2 and schizophrenia. All three SREB genes are highly expressed in differentiated hippocampal neural stem cells. Furthermore, 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 208972198  13 KAEKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHP--LMAALPAYFAKSATiyNPIIYVFMNRQ 80
Cdd:cd15005  257 KMEKRLTRMFYAITLLFLLLWSPYIVACYIRVFVRGYAVPQgfLTAAVWMTFAQAGV--NPIVCFFFNRE 324

serotonin receptor subtypes 1, 5 and 7, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes serotonin receptor subtypes 1, 5, and 7 that are activated by the neurotransmitter serotonin. The 5-HT1 and 5-HT5 receptors mediate inhibitory neurotransmission by coupling to G proteins of the G(i/o) family. The 5-HT1 receptor subfamily includes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. There is no 5-HT1C receptor subtype, as it has been reclassified as 5-HT2C receptor. The 5-HT5A and 5-HT5B receptors have been cloned from rat and mouse, but only the 5-HT5A isoform has been identified in human because of the presence of premature stop codons in the human 5-HT5B gene, which prevents a functional receptor from being expressed. The 5-HT7 receptor is coupled to Gs, which positively stimulates adenylate cyclase activity, leading to increased intracellular cAMP formation and calcium influx. 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 208972198  15 EKEVTRMVVVMIMAYCVCWGPY*FFACFAAAHPGYAFHPLMAALPAYFAKSATIYNPIIYVFMNR 79
Cdd:cd15064  188 ERKAAKTLGIILGAFIVCWLPFFLVALIVPLCSHCWIPLALKSFFLWLGYFNSLINPLIYTFFNK 252

complement component 5a anaphylatoxin chemotactic receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The anaphylatoxin receptors are a group of G-protein coupled receptors which bind anaphylatoxins; members of this group include C3a receptors and C5a receptors. Anaphylatoxins are also known as complement peptides (C3a, C4a and C5a) that are produced from the activation of the complement system cascade. These complement anaphylatoxins can trigger degranulation of endothelial cells, mast cells, or phagocytes, which induce a local inflammatory response and stimulate smooth muscle cell contraction, histamine release, and increased vascular permeability. They are potent mediators involved in chemotaxis, inflammation, and generation of cytotoxic oxygen-derived free radicals. In humans, a single receptor for C3a (C3AR1) and two receptors for C5a (C5AR1 and C5AR2, also known as C5L2 or GPR77) have been identified, but there is no known receptor for C4a.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 208972198   8 SESTQKAEKeVTRMVVVMIMAYCVCWGPY*FFACFAAAH-PGYAFHPLMAALPAYFAKSATIY---NPIIYVFMNRQ 80
Cdd:cd15114  194 SRRRQKSRR-TLKVVTAVVVGFFLCWTPYHVVGLIIAASaPNSRLLANALKADPLTVSLAYINsclNPIIYVVAGRG 269