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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1242853229 375 ICTAVYLLSWVPFFfeIFNVTR--------ILVFRYFFLVGH---AANPIIYSVVNIKIRNA 425
Cdd:cd15065   240 IIMGVFLICWLPFF--IINIIAafcktcipPKCFKILTWLGYfnsCLNPIIYSIFNSEFRRA 299

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  24 GNALIVAVYVSNFRKffHSK---YILALSIADLVVNVLIVPYSAVFQL---RLVTLDFICHGMEVIRHTSVGFSNLILAL 97
Cdd:pfam00001   1 GNLLVILVILRNKKL--RTPtniFLLNLAVADLLFSLLTLPFWLVYYLnhgDWPFGSALCKIVGALFVVNGYASILLLTA 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  98 IAMERLLMIWKPLESKA-MSEKYKLIPIFVVLAISIVCGIPAGaiyqvtdkaydFNGSSNSSESATEPFC--QYTTEILG 174
Cdd:pfam00001  79 ISIDRYLAIVHPLRYKRrRTPRRAKVLILVIWVLALLLSLPPL-----------LFGWTLTVPEGNVTVCfiDFPEDLSK 147

                         170       180
                  ....*....|....*....|...
gi 1242853229 175 KGMSEVYRNVLAFVILLefLVMI 197
Cdd:pfam00001 148 PVSYTLLISVLGFLLPL--LVIL 168

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229   9 TFLVFVSLLAIVGIVGNALIVAVYVSNfrKFFHSK---YILALSIADLVVNVLIVPYSAVfqlRLVTLD-----FICHGM 80
Cdd:cd14993     2 VLIVLYVVVFLLALVGNSLVIAVVLRN--KHMRTVtnyFLVNLAVADLLVSLFCMPLTLL---ENVYRPwvfgeVLCKAV 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  81 EVIRHTSVGFSNLILALIAMERLLMIWKPLESKAMSEKYK-LIPIFVVLAISIVCGIPAGAIYQVTDKAYDFNGSSnsse 159
Cdd:cd14993    77 PYLQGVSVSASVLTLVAISIDRYLAICYPLKARRVSTKRRaRIIIVAIWVIAIIIMLPLLVVYELEEIISSEPGTI---- 152

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1242853229 160 saTEPFCqytTEILGKGMSEVYRNVLAFVIL--LEFLVMIVVYVLVYVLVCRQKLRLRRYSLNSVTKT----NKRMVTK 232
Cdd:cd14993   153 --TIYIC---TEDWPSPELRKAYNVALFVVLyvLPLLIISVAYSLIGRRLWRRKPPGDRGSANSTSSRrilrSKKKVAR 226

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  15 SLLAIVGIVGNALIVAVYVSNFR-KFFHSKYILALSIADLVVNVLIVPYSAVFQL--RLVTLDFICHGMEVIRHTSVGFS 91
Cdd:cd15206     8 SVIFLLAVVGNILVIVTLVQNKRmRTVTNVFLLNLAVSDLLLAVFCMPFTLVGQLlrNFIFGEVMCKLIPYFQAVSVSVS 87

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1242853229  92 NLILALIAMERLLMIWKPLESKA---MSEKYKLIPIFVVLAISIVCGIPA 138
Cdd:cd15206    88 TFTLVAISLERYFAICHPLKSRVwqtLSHAYKVIAGIWLLSFLIMSPILV 137

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  10 FLVFVSLLAIVGIVGNALIVAVYVSNFRKFFHSKYILALSIADLVVNVLIVPYSAVFQLRLVTLDFICHGMEVIRHTSVG 89
Cdd:cd14978     3 YGYVLPVICIFGIIGNILNLVVLTRKSMRSSTNVYLAALAVSDILVLLSALPLFLLPYIADYSSSFLSYFYAYFLPYIYP 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  90 FSNL-------ILALIAMERLLMIWKPLESKAM-SEKYKLIPIFVVLAISIVCGIPAGAIYQVTDkaydfngsSNSSESA 161
Cdd:cd14978    83 LANTfqtasvwLTVALTVERYIAVCHPLKARTWcTPRRARRVILIIIIFSLLLNLPRFFEYEVVE--------CENCNNN 154

                         170       180       190
                  ....*....|....*....|....*....|....*...
gi 1242853229 162 TEPFCQYTTEILGKGMSEVYRNVL--AFVILLEFLVMI 197
Cdd:cd14978   155 SYYYVIPTLLRQNETYLLKYYFWLyaIFVVLLPFILLL 192

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLAIVGIVGNAL-IVAVYVSNFRKFFHSKYILALSIADLVVNVLIVPYSAV--FQLRLVTLDFICHGMEVIRHTSV 88
Cdd:cd15210     5 VWGIVFMVVGVPGNLLtVLALLRSKKLRTRTNAFIINLSISDLLFCAFNLPLAAStfLHQAWIHGETLCRVFPLLRYGLV 84

                          90
                  ....*....|....*...
gi 1242853229  89 GFSNLILALIAMERLLMI 106
Cdd:cd15210    85 AVSLLTLVLITLNRYILI 102

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLAIVGIVGNAL-IVAVYVSNFRKFFHSKYILALSIADLVVNVLIVPYSAVFQLRLVTLDF------ICHGMEVIR 84
Cdd:cd15067     4 VVLSLFCLVTVAGNLLvILAVLRERYLRTVTNYFIVSLAVADLLVGSIVMPFSILHEMTGGYWLFgrdwcdVWHSFDVLA 83

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1242853229  85 HTSvgfSNLILALIAMERLLMIWKPLE-SKAMSEKYKLIPIFVVLAISIVCGIPAGAIYQVTDKAY 149
Cdd:cd15067    84 STA---SILNLCVISLDRYWAITDPISyPSRMTKRRALIMIALVWICSALISFPAIAWWRAVDPGP 146

classical and atypical chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. In addition to these classical chemokine receptors, there exists a subfamily of atypical chemokine receptors (ACKRs) that are unable to couple to G-proteins and, instead, they preferentially mediate beta-arrestin dependent processes, such as receptor internalization, after ligand binding. The classical chemokine receptors contain a conserved DRYLAIV motif in the second intracellular loop, which is required for G-protein coupling. However, the ACKRs lack this conserved motif and fail to couple to G-proteins and induce classical GPCR signaling. Five receptors have been identified for the ACKR family, including CC-chemokine receptors like 1 and 2 (CCRL1 and CCRL2), CXCR7, Duffy antigen receptor for chemokine (DARC), and D6. Both ACKR1 (DARC) and ACKR3 (CXCR7) show low sequence homology to the classic chemokine receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLAIVGIVGNALIVAVYVsNFRKFFHS--KYILALSIADLVVnVLIVPYSAVFQLRL-VTLDFICHGMEVIRHTSV 88
Cdd:cd14984     5 VLYSLVFLLGLVGNSLVLLVLL-YYRKLRSMtdVYLLNLALADLLF-VLTLPFWAVYAADGwVFGSFLCKLVSALYTINF 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  89 GFSNLILALIAMERLLMIWKPLES-KAMSEKYKLIPIFVVLAISIVCGIPAGAIYQVtdkaydfngSSNSSESATEPFCQ 167
Cdd:cd14984    83 YSGILFLACISIDRYLAIVHAVSAlRARTLLHGKLTCLGVWALALLLSLPEFIFSQV---------SEENGSSICSYDYP 153

                         170       180       190
                  ....*....|....*....|....*....|
gi 1242853229 168 YTTEILGKGMSEVYRNVLAFviLLEFLVMI 197
Cdd:cd14984   154 EDTATTWKTLLRLLQNILGF--LLPLLVML 181

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        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLAIVGIVGNALIVAVYVSNFRKFFHSK--YILALSIADLVVNVLIVPysavFQLRLVTLD------FICHGMEVI 83
Cdd:cd15097     5 VVFSLIFLLGTVGNSLVLAVLLRSGQSGHNTTnlFILNLSVADLCFILFCVP----FQATIYSLEgwvfgsFLCKAVHFF 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1242853229  84 RHTSVGFSNLILALIAMERLLMIWKPLESKAMSEKYK-LIPIFVVLAISIVCGIPAGAIYQVTDKA 148
Cdd:cd15097    81 IYLTMYASSFTLAAVSVDRYLAIRYPLRSRELRTPRNaVAAIALIWGLSLLFAGPYLSYYDLIDYA 146

atypical chemokine receptor 4, member of the class A family of seven-transmembrane G protein-coupled receptors; ACKR4 was first reported to bind several CC chemokines including CCL19, CCL21, and CCL25 and was originally designated CCR11. AKCR4 is unable to couple to G-protein and, instead, it preferentially mediates beta-arrestin dependent processes, such as receptor internalization, after ligand binding. Thus, ACKR4 may act as a scavenger receptor to suppress the effects of proinflammatory chemokines. Unlike the classical chemokine receptors that contain a conserved DRYLAIV motif in the second intracellular loop, which is required for G-protein coupling, the ACKRs lack this conserved motif and fail to couple to G-proteins and induce classical GPCR signaling. Five receptors have been identified for the ACKR family, including CC-chemokine receptors like 1 and 2 (CCRL1 and CCRL2), CXCR7, Duffy antigen receptor for chemokine (DARC), and D6. Both ACKR1 (DARC) and ACKR3 (CXCR7) show low sequence homology to the classic chemokine receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLAIVGIVGNALIVAVYVSNFR-KFFHSKYILALSIADLVVnVLIVPYSAV-----FQLRLVTLDfICHGMEVIRH 85
Cdd:cd15176     5 VFYTIALVVGLAGNSLVVAIYAYYKKlKTKTDVYILNLAVADLLL-LFTLPFWAAdavngWVLGTAMCK-ITSALYTMNF 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  86 TSvgfSNLILALIAMERLLMIWKpLESKAMSEKYKLIPIFVVLAISIVCGIPAGAIYQVtdkaydfngSSNSSESATEPF 165
Cdd:cd15176    83 SC---GMQFLACISVDRYVAITK-ATSRQFTGKHCWIVCLCVWLLAILLSIPDLVFSTV---------RENSDRYRCLPV 149

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1242853229 166 CQYTTEILGKGMSEVYRNVLAFVilLEFLVMI 197
Cdd:cd15176   150 FPPSLVTSAKATIQILEVLLGFV--LPFLVMV 179

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 1242853229  12 VFVSLLAIVGIVGNALIVAVYVS--NFRKFFhSKYILALSIADLVVNVLIVPYS--AVFQLRLVTLDFICHGMEVIRHTS 87
Cdd:cd14992     5 VALVVIILVSVVGNFIVIAALARhkNLRGAT-NYFIASLAISDLLMALFCTPFNftYVVSLSWEYGHFLCKIVNYLRTVS 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  88 VGFSNLILALIAMERLLMIWKPLESKAMSEKYKLIPIF-VVLAISIVCGIPAGaIYQVTDKAYDFNGSsnssesaTEPFC 166
Cdd:cd14992    84 VYASSLTLTAIAFDRYFAIIHPLKPRHRQSYTTTVIIIiTIWVVSLLLAIPQL-YYATTEVLFSVKNQ-------EKIFC 155

                         170       180       190
                  ....*....|....*....|....*....|..
gi 1242853229 167 QYTTEILGKGMSEVYRnVLAFVIL--LEFLVM 196
Cdd:cd14992   156 CQIPPVDNKTYEKVYF-LLIFVVIfvLPLIVM 186

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  11 LVFVSLLAIVGIVGNALIVAVYVSNFR-KFFHSKYILALSIADLVVNVLIVPYSAVFQLrLVTLDF---ICHGMEVIRHT 86
Cdd:cd15979     4 ILLYSVIFLLSVFGNMLIIVVLGLNKRlRTVTNSFLLSLALSDLMLAVFCMPFTLIPNL-MGTFIFgevICKAVAYLMGV 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1242853229  87 SVGFSNLILALIAMERLLMIWKPLESKA---MSEKYKLIPIFVVLAISIVCGIP 137
Cdd:cd15979    83 SVSVSTFSLVAIAIERYSAICNPLQSRVwqtRSHAYRVIAATWLLSGLIMIPYP 136

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  10 FLVFVSLLAIVGIVGNALIVAVYVSNFRKFFHSKYILA-LSIADLVVNVLIVPYSAVFQL--RLVTLDFICHGMEVIRHT 86
Cdd:cd15012     2 FIILYTLVFCCCFFGNLLVILVVTSHRRMRTITNFFLAnLAVADLCVGIFCVLQNLSIYLipSWPFGEVLCRMYQFVHSL 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1242853229  87 SVGFSNLILALIAMERLLMIWKPLESK-AMSEKYKLIPIFVVLAISIVCGIPAGAIYQ 143
Cdd:cd15012    82 SYTASIGILVVISVERYIAILHPLRCKqLLTAARLRVTIVTVWLTSAVYNTPYFVFSQ 139

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229   8 LTFLVFvsllaIVGIVGNALI-VAVYVSNFRKFFHSKYILALSIADLVVNVLIVPYSAVFQLrLVTLDFICHGMEVIRH- 85
Cdd:cd15208     6 LYILVF-----IVGLVGNVLVcFAVWRNHHMRTVTNYFIVNLSLADFLVIIICLPATLLVDV-TETWFFGQVLCKIIPYl 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1242853229  86 --TSVGFSNLILALIAMERLLMIWKPLESKAMSEKYKLIpIFVVLAISIVCGIPAGAIYQVT 145
Cdd:cd15208    80 qtVSVSVSVLTLSCIALDRWYAICHPLMFKSTAKRARVS-ILIIWIVSLLIMIPQAIVMECS 140

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  15 SLLAIVGIVGNALIVAVYVSNFRkfFHSK---YILALSIADLVVNVLIVPYSAVFQL--RLVTLDFICHGMEVIRHTSVG 89
Cdd:cd15389     8 SIIIVISLFGNSLVCHVIFKNKR--MHTAtnlFIVNLAVSDILITLLNTPFTLVRFVnsTWVFGKIMCHLSRFAQYCSVY 85

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1242853229  90 FSNLILALIAMERLLMIWKPLESKaMSEKYKLIPIFVVLAISIVCGIPAgAIYQ 143
Cdd:cd15389    86 VSTLTLTAIALDRHRVILHPLKPR-ITPCQGVVVIAIIWIMASCLSLPH-AIYQ 137

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229   8 LTFLVFVSLLAIVGIVGNALIVAVYVSNFRKFFHSKYILA-LSIADLVVNVLIVPYSAVFQLRLVTL--DFICHGMEVIR 84
Cdd:cd15195     1 LVRVLVTWVLFVISAAGNLTVLIQLFRRRRAKSHIQILIMhLALADLMVTFFNMPMDAVWNYTVEWLagDLMCRVMMFLK 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1242853229  85 HTSVGFSNLILALIAMERLLMIWKPLeSKAMSEKYKLIPIFVVLAISIVCGIPAGAIYQVTDKAYD 150
Cdd:cd15195    81 QFGMYLSSFMLVVIALDRVFAILSPL-SANQARKRVKIMLTVAWVLSALCSIPQSFIFSVLRKMPE 145

neuropeptide Y receptor type 5, 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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  12 VFVSLLaivGIVGNALIVAVYVSNFRKffhsKYILALSIADLVV-NVLIVPYSAVFQLRLVTLD------FICHGMEVIR 84
Cdd:cd15398     8 TFISLL---GFLGNLLILTALTKKWKQ----KTIINFLIGNLAFsDILVVLFCSPFTLTCVLLDqwifgeVMCHIVPFLQ 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1242853229  85 HTSVGFSNLILALIAMERLLMIWKPLESK-AMSEKYKLIPIFVVLAISIVCGIP 137
Cdd:cd15398    81 CVSVMVSTLMLMSIAIVRYHMIKHPLSNHlTANHGYFLLGTVWTLGFTICSPLP 134

neurotensin receptors and related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily includes the neurotensin receptors and related G-protein coupled receptors, including neuromedin U receptors, growth hormone secretagogue receptor, motilin receptor, the putative GPR39 and the capa receptors from insects. These receptors all bind peptide hormones with diverse physiological effects. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229   7 TLTFLvfvsLLAIVGIVGNALIVAVYVSNFRKFFHSKYILA-LSIADLVVNVLIVP---YSAVFQLRLVTLDFICHGMEV 82
Cdd:cd14979     4 TAIYV----AIFVVGIVGNLLTCIVIARHKSLRTTTNYYLFsLAVSDLLILLVGLPvelYNFWWQYPWAFGDGGCKLYYF 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  83 IRHTSVGFSNLILALIAMERLLMIWKPLESKAMSEKYKLIP-IFVVLAISIVCGIPAGAIYQVTDKAYDFNGSSNSSEsa 161
Cdd:cd14979    80 LFEACTYATVLTIVALSVERYVAICHPLKAKTLVTKRRVKRfILAIWLVSILCAIPILFLMGIQYLNGPLPGPVPDSA-- 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229 162 tepFCQYTTeilgkgMSEVYRNVLAFVILLEFLVMIvVYVLVYVLVCRQKLRLRRYSLNSVTKTNkrmvTKNSETSLTSS 241
Cdd:cd14979   158 ---VCTLVV------DRSTFKYVFQVSTFIFFVLPM-FVISILYFRIGVKLRSMRNIKKGTRAQG----TRNVELSLSQQ 223

                  .
gi 1242853229 242 S 242
Cdd:cd14979   224 A 224

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  10 FLVFVSLLAIVG-IVGNALIVaVYVSNFRKFFH-SKY-ILALSIADLVVNVLIVPYSAVFQL--RLVTLDFICH---GME 81
Cdd:cd15329     2 LIGIVLLIIILGtVVGNALVI-IAVCLVKKLRTpSNYlIVSLAVSDLLVALLVMPLAIIYELsgYWPFGEILCDvwiSFD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  82 VIRHTSvgfSNLILALIAMERLLMIWKPLESkAMSEKYKLIP--IFVVLAISIVCGIPAGAIYQvtdkaydfngssnsSE 159
Cdd:cd15329    81 VLLCTA---SILNLCAISVDRYLVITRPLTY-AVKRTPKRMAlmIAIVWLLSALISIPPLFGWK--------------NK 142

                         170       180       190
                  ....*....|....*....|....*....|....*...
gi 1242853229 160 SATEPFCQYTTEILgkgmSEVYRNVLAFVILLefLVMI 197
Cdd:cd15329   143 VNDPGVCQVSQDFG----YQIYATFGAFYIPL--IVML 174

neuropeptide FF receptor 2, member of the class A family of seven-transmembrane G protein-coupled receptors; Neuropeptide FF (NPFF) is a mammalian octapeptide that belongs to a family of neuropeptides containing an RF-amide motif at their C-terminus that have 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 these peptides 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. NPFF has been shown to inhibit adenylate cyclase via the Gi protein coupled to NPFF1-R.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  10 FLVFVSLLAIVGIVGNALIVAVYVSNfrKFFHSK---YILALSIADLVVNVLIVPYSAVFQLrLVTLDF---ICHGMEVI 83
Cdd:cd15980     3 FIASYLLIFLLCMMGNGVVCFIVLRS--KHMRTVtnlFILNLAISDLLVGIFCMPTTLLDNI-IAGWPFgstVCKMSGMV 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229  84 RHTSVGFSNLILALIAMERLLMIWKPLESK-AMSEKYKLIPIFVVLAISIVCgiPAGAIYQVTDKAYDFNGSSNSSEsaT 162
Cdd:cd15980    80 QGISVSASVFTLVAIAVDRFRCIVYPFKQKlTISTAVVIIVIIWVLAIAIMC--PSAVMLHVQEEKNYRVVLGSQNK--T 155

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1242853229 163 EPFCQYTTEILGKGMSEVYRNVLAFVILLEFLVMI 197
Cdd:cd15980   156 SPVYWCREDWPNQEMRKIYTTVLFANIYLAPLSLI 190

octopamine receptors in invertebrates, member of the class A family of seven-transmembrane G protein-coupled receptors; G-protein coupled receptor for octopamine (OA), which functions as a neurotransmitter, neurohormone, and neuromodulator in invertebrate nervous system. Octopamine (also known as beta, 4-dihydroxyphenethylamine) is an endogenous trace amine that is highly similar to norepinephrine, but lacks a hydroxyl group, and has effects on the adrenergic and dopaminergic nervous systems. Based on the pharmacological and signaling profiles, the octopamine receptors can be classified into at least two groups: OA1 receptors elevate intracellular calcium levels in muscle, whereas OA2 receptors activate adenylate cyclase and increase cAMP production.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1242853229   8 LTFLVFVSLLAIVGIVGNAL-IVAVYVSNFRKFFHSKYILALSIADLVVNVLIVPYSAVFQLRLVTL--DFICH---GME 81
Cdd:cd15063     1 LISLLVLTFLNVLVVLGNLLvIAAVLCSRKLRTVTNLFIVSLACADLLVGTLVLPFSAVNEVLDVWIfgHTWCQiwlAVD 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1242853229  82 VIRHTSvgfSNLILALIAMERLLMIWKPLESKA-MSEKYKLIPIFVVLAIS-IVCGIPAGAIYQVTDKAYDFNGSSNSS 158
Cdd:cd15063    81 VWMCTA---SILNLCAISLDRYLAITRPIRYPSlMSTKRAKCLIAGVWVLSfVICFPPLVGWNDGKDGIMDYSGSSSLP 156