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 347453047   1 CHFRSVVCLDYMVFFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLP 80
Cdd:cd15070  153 CQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLALVLFLFAVCWLP 232

                         90       100
                 ....*....|....*....|....*..
gi 347453047  81 LSIINFVSYFQVKIPEVAMCLGILLSH 107
Cdd:cd15070  233 LSIINCVVYFNPKVPKIALYLGILLSH 259

adenosine receptor subtype A3, member of the class A family of seven-transmembrane G protein-coupled receptors; The A3 receptor, a member of the adenosine receptor family of G protein-coupled receptors, is coupled to G proteins of the inhibitory G(i) family, which lead to inhibition of adenylate cyclase and thereby lowering the intracellular cAMP levels. The A3 receptor has a sustained protective function in the heart during cardiac ischemia and contributes to inhibition of neutrophil degranulation in neutrophil-mediated tissue injury. Moreover, activation of A3 receptor by adenosine protects astrocytes from cell death induced by hypoxia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCLDYMVFFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLP 80
Cdd:cd15070  153 CQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLALVLFLFAVCWLP 232

                         90       100
                 ....*....|....*....|....*..
gi 347453047  81 LSIINFVSYFQVKIPEVAMCLGILLSH 107
Cdd:cd15070  233 LSIINCVVYFNPKVPKIALYLGILLSH 259

adenosine receptor subtype A3, member of the class A family of seven-transmembrane G protein-coupled receptors; The A3 receptor, a member of the adenosine receptor family of G protein-coupled receptors, is coupled to G proteins of the inhibitory G(i) family, which lead to inhibition of adenylate cyclase and thereby lowering the intracellular cAMP levels. The A3 receptor has a sustained protective function in the heart during cardiac ischemia and contributes to inhibition of neutrophil degranulation in neutrophil-mediated tissue injury. Moreover, activation of A3 receptor by adenosine protects astrocytes from cell death induced by hypoxia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCLDYMVFFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLP 80
Cdd:cd15070  153 CQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLALVLFLFAVCWLP 232

                         90       100
                 ....*....|....*....|....*..
gi 347453047  81 LSIINFVSYFQVKIPEVAMCLGILLSH 107
Cdd:cd15070  233 LSIINCVVYFNPKVPKIALYLGILLSH 259

adenosine receptor subtype A1, member of the class A family of seven-transmembrane G protein-coupled receptors; The adenosine A1 receptor, a member of the adenosine receptor family of G protein-coupled receptors, binds adenosine as its endogenous ligand. The A1 receptor has primarily inhibitory function on the tissues in which it is located. The A1 receptor slows metabolic activity in the brain and has a strong anti-adrenergic effects in the heart. Thus, it antagonizes beta1-adrenergic receptor-induced stimulation and thereby reduces cardiac contractility. The A1 receptor preferentially couples to G proteins of the G(i/o) family, which lead to inhibition of adenylate cyclase and thereby lowering the intracellular cAMP levels.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCLDYMVFFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGF-RETRAFYGREFKTAKSLFLVLFLFAVCWL 79
Cdd:cd15071  160 CQFETVISMEYMVYFNFFVWVLPPLLLMLLIYLEVFYLIRKQLNKKVSSSsSDPQKYYGKELKIAKSLALILFLFALSWL 239

                         90       100       110
                 ....*....|....*....|....*....|
gi 347453047  80 PLSIINFVSYF--QVKIPEVAMCLGILLSH 107
Cdd:cd15071  240 PLHILNCITLFcpSCKKPMILTYIAIFLTH 269

adenosine receptor subtype A2A, member of the class A family of seven-transmembrane G protein-coupled receptors; The A2A receptor, a member of the adenosine receptor family of G protein-coupled receptors, binds adenosine as its endogenous ligand and is involved in regulating myocardial oxygen consumption and coronary blood flow. High-affinity A2A and low-affinity A2B receptors are preferentially coupled to G proteins of the stimulatory (Gs) family, which lead to activation of adenylate cyclase and thereby increasing the intracellular cAMP levels. The A2A receptor activation protects against tissue injury and acts as anti-inflammatory agent. In human skin endothelial cells, activation of A2B receptor, but not the A2A receptor, promotes angiogenesis. Alternatively, activated A2A receptor, but not the A2B receptor, promotes angiogenesis in human umbilical vein and lung microvascular endothelial cells. The A2A receptor alters cardiac contractility indirectly by modulating the anti-adrenergic effect of A1 receptor, while the A2B receptor exerts direct effects on cardiac contractile function, but does not modulate beta-adrenergic or A1 anti-adrenergic effects.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCLDYMVFFSFITWILIPLVVMCVIYLDIFYIIQNKL----SQNLSGFReTRAFYGREFKTAKSLFLVLFLFAV 76
Cdd:cd15068  160 CLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLkqmeSQPLPGER-ARSTLQKEVHAAKSLAIIVGLFAL 238

                         90       100       110
                 ....*....|....*....|....*....|....
gi 347453047  77 CWLPLSIINFVSYF---QVKIPEVAMCLGILLSH 107
Cdd:cd15068  239 CWLPLHIINCFTFFcpdCSHAPLWLMYLAIVLSH 272

amine receptors and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; Amine receptors of the class A family of GPCRs include adrenoceptors, 5-HT (serotonin) receptors, muscarinic cholinergic receptors, dopamine receptors, histamine receptors, and trace amine receptors. The receptors of amine subfamily are major therapeutic targets for the treatment of neurological disorders and psychiatric diseases. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047  11 YMVFFSFITWILIPLVVMCVIYLDIFYIIQnklsqnlsgfretrafygREFKTAKSLFLVLFLFAVCWLPLSIINFVSYF 90
Cdd:cd14967  158 IYVLVSSVISFFIPLLIMIVLYARIFRVAR------------------RELKAAKTLAIIVGAFLLCWLPFFIIYLVSAF 219

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 347453047  11 YMVFFSFITWiLIPLVVMCVIYLDIFYIIQ------NKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLP 80
Cdd:cd15051  164 YVLLVAIGTF-YLPLLIMCGVYLRIFRIAReqakriNALTPASTANSSKSAATAREHKATVTLAAVLGAFIICWFP 238

neuropeptide FF receptors, 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 347453047  17 FITWILIPLVVMCVIYLDIFY-IIQNKLSQNLSGFRETRAFY-GREFKTAKSLFLVLFLFAVCWLPLSIINFVSYF 90
Cdd:cd15207  171 FVLCYVAPLLIIAVLYVRIGYrLWFKPVPGGGSASREAQAAVsKKKVRVIKMLIVVVVLFALSWLPLHTVTMLDDF 246

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCLDYMVFFS--FITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAfygREFKTAKSLFLVLFLFAVCW 78
Cdd:cd15096  154 CTFLTEVGTAAQTFFTsfFLFSYLIPLTLICVLYMLMLRRLRRQKSPGGRRSAESQR---GKRRVTRLVVVVVVVFAICW 230

                         90
                 ....*....|....
gi 347453047  79 LPLSIINFVSYFQV 92
Cdd:cd15096  231 LPIHIILLLKYYGV 244

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 347453047  14 FFSFITWILIPLVVMCVIYLDIFY---IIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLPLSIINFVSYF 90
Cdd:cd14993  172 VALFVVLYVLPLLIISVAYSLIGRrlwRRKPPGDRGSANSTSSRRILRSKKKVARMLIVVVVLFALSWLPYYVLSILLDF 251

                 .
gi 347453047  91 Q 91
Cdd:cd14993  252 G 252

beta adrenergic receptors (adrenoceptors), member of the class A family of seven-transmembrane G protein-coupled receptors; The beta adrenergic receptor (beta adrenoceptor), also known as beta AR, is activated by hormone adrenaline (epinephrine) and plays important roles in regulating cardiac function and heart rate, as well as pulmonary physiology. The human heart contains three subtypes of the beta AR: beta-1 AR, beta-2 AR, and beta-3 AR. Beta-1 AR and beta-2 AR, which expressed at about a ratio of 70:30, are the major subtypes involved in modulating cardiac contractility and heart rate by positively stimulating the G(s) protein-adenylate cyclase-cAMP-PKA signaling pathway. In contrast, beta-3 AR produces negative inotropic effects by activating inhibitory G(i) proteins. The aberrant expression of beta-ARs can lead to cardiac dysfunction such as arrhythmias or heart failure. 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 347453047  11 YMVFFSFITWiLIPLVVMCVIYLDIFYIIQNKL-----------SQNL------------SGFRETRAFYGREFKTAKSL 67
Cdd:cd15058  166 YAIASSVVSF-YIPLLIMIFVYARVFLIATRQLqlidkrrlrfqSECPapqttspegkrsSGRRPSRLTVVKEHKALKTL 244

                         90       100
                 ....*....|....*....|....*...
gi 347453047  68 FLVLFLFAVCWLPLSIINFVSYFQVKIP 95
Cdd:cd15058  245 GIIMGTFTLCWLPFFIANIINVFNRNLP 272

relaxin receptor 2 (or LGR8), member of the class A family of seven-transmembrane G protein-coupled receptors; Relaxin is a member of the insulin superfamily that has diverse actions in both reproductive and non-reproductive tissues. The relaxin-like peptide family includes relaxin-1, relaxin-2, and the insulin-like (INSL) peptides such as INSL3, INSL4, INSL5 and INSL6. The relaxin family peptides share high structural similarity, but low sequence similarity, and exert their physiological functions by activating a group of four G protein-coupled receptors, RXFP1-4. INSL3 is the endogenous ligand for RXFP2, which couples to the G(s) protein to increase intracellular cAMP levels, but also to the GoB protein to decrease cAMP formation. RXFP2 (or LGR8) is expressed in various tissues including the brain, kidney, muscle, testis, thyroid, uterus, and peripheral blood cells, among others.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 347453047  22 LIPLVVMCVIYLDIFYIIQNKLSQNlsgfRETRAFYGREFKTAKSLFLVLFLFAVCWLPLSIINFVSYFQVKIP 95
Cdd:cd15966  184 LLAFIIIVFSYSSMFCSIQKTGLQT----TEVRSHIHRDVAVANRFFFIVFSDAICWIPIFLLKILSLFQVEIP 253

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 347453047  14 FFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAFYGREF----KTAKSLFLVLFLFAVCWLPLSIINFVSY 89
Cdd:cd15203  169 ISVLVLQFVIPLLIISFCYFRISLKLRKRVKKKRGKRTLSSRRRRSELrrkrRTNRLLIAMVVVFAVCWLPLNLFNLLRD 248

                 ....*.
gi 347453047  90 FQVKIP 95
Cdd:cd15203  249 FEPLPQ 254

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047  11 YMVFFSFITWIlIPLVVMCVIYLDIFYIIQ---------------NKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFA 75
Cdd:cd15065  168 YAVVSSLISFY-IPCLVMLLIYSRLYLYARkhvvniksqklpsesGSKFQVPSLSSKHNNQGVSDHKAAVTLGIIMGVFL 246

                         90
                 ....*....|....*
gi 347453047  76 VCWLPLSIINFVSYF 90
Cdd:cd15065  247 ICWLPFFIINIIAAF 261

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 347453047  11 YMVFFSFITWiLIPLVVMCVIYLDIFYII--QNKLSQNLSGFRETRAFYGREfKTAKSLFLVLFLFAVCWLPLSIIN 85
Cdd:cd15095  166 YMIYTVLLTY-VIPLAIIAVCYGLILRRLwrRSVDGNNQSEQLSERALRQKR-KVTRMVIVVVVLFAICWLPNHVLN 240

somatostatin receptor type 2, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs), which display strong sequence similarity with opioid receptors, binds somatostatin, a polypeptide hormone that regulates a wide variety of physiological such as neurotransmission, endocrine secretion, cell proliferation, and smooth muscle contractility. SSTRs are composed of five distinct subtypes (SSTR1-5) which are encoded by separate genes on different chromosomes. SSTR2 plays critical roles in growth hormone secretion, glucagon secretion, and immune responses. SSTR2 is expressed in the normal human pituitary and in nearly all pituitary growth hormone adenomas.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 347453047  13 VFFSFITWILIPLVVMCVIYLdiFYIIQNKLSQNLSGFRETRAfygREFKTAKSLFLVLFLFAVCWLPLSIINFVS 88
Cdd:cd15971  165 IIYTFILGFFVPLTIICLCYL--FIIIKVKSSGIRVGSSKRKK---SEKKVTRMVSIVVAVFVFCWLPFYIFNVSS 235

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 347453047  11 YMVFFSFITWILIPLVVMCVIYLDIFYIIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLPLSIINFVSYF 90
Cdd:cd15389  167 YLDLATFILQYVLPLLIIGVAYTRVAKKLWLRNAIGDVTTEQYVAQRRKKKKTIKMLMLVVLLFAICWLPLNCYHVLLSS 246

                 .
gi 347453047  91 Q 91
Cdd:cd15389  247 H 247

trace amine-associated receptor 1 and similar receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The trace amine-associated receptor 1 (TAAR1) is one of the 15 identified trace amine-associated receptor subtypes, which form a distinct subfamily within the class A G protein-coupled receptor family. Trace amines are endogenous amines of unknown function that have strong structural and metabolic similarity to classical monoamine neurotransmitters (serotonin, noradrenaline, adrenaline, dopamine, and histamine), which play critical roles in human and animal physiological activities such as cognition, consciousness, mood, motivation, perception, and autonomic responses. However, trace amines are found in the mammalian brain at very low concentrations compared to classical monoamines. TAAR1 is coupled to the Gs protein, which leads to activation of adenylate cyclase, and is thought to play functional role in the regulation of brain monoamines. TAAR1 is also shown to be activated by psychoactive compounds such as Ecstasy (MDMA), amphetamine and LSD. 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 347453047   3 FRSVVCLDYMVFFSFitwiLIPLVVMCVIYLDIFYIIQNKL-SQNLSGFRETRAFYGREFKTAKSLFLVLFLFAVCWLPL 81
Cdd:cd15314  159 FFSKVSSVVGSVFSF----YIPAVIMLCIYLKIFLVAQRQArSIQSARTKSGASSSKMERKATKTLAIVMGVFLLCWTPF 234

                         90       100       110
                 ....*....|....*....|....*....|
gi 347453047  82 SIIN-FVSYFQVKIP----EVAMCLGILLS 106
Cdd:cd15314  235 FLCNiIDPFINYSIPpvliEVLNWLGYSNS 264

beta-2 adrenergic receptors (adrenoceptors), member of the class A family of seven-transmembrane G protein-coupled receptors; Beta-2 AR is activated by adrenaline that plays important roles in cardiac function and pulmonary physiology. While beta-1 AR and beta-2 AR are the major subtypes involved in modulating cardiac contractility and heart rate by positively stimulating the G(s) protein-adenylate cyclase-cAMP-PKA signaling pathway, beta-2 AR can couple to both G(s) and G(i) proteins in the heart. Moreover, beta-2 AR activation leads to smooth muscle relaxation and bronchodilation in the lung. The beta adrenergic receptors are a subfamily of the class A rhodopsin-like G protein-coupled receptors.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047  16 SFITWILIPLVVMCVIYLDIF-------------------YIIQNKLSQNLSGFRETRAFYGREFKTAKSLFLVLFLFAV 76
Cdd:cd15957  170 SSIVSFYVPLVIMVFVYSRVFqeakrqlqkidksegrfhnQNIDQNGSGGGGGNRRRSKFCLKEHKALKTLGIIMGTFTL 249

                         90
                 ....*....|....*...
gi 347453047  77 CWLPLSIINFVSYFQVKI 94
Cdd:cd15957  250 CWLPFFIVNIVHVIQDNL 267

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347453047   1 CHFRSVVCldYMVFFSFITWiLIPLVVMCVIYLDIFYIIqnklsqnlsgfretrafyGREFKTAKSLFLVLFLFAVCWLP 80
Cdd:cd15067  152 CLFTDDSG--YLIFSSCVSF-YIPLVVMLFTYYRIYRAA------------------AKEQKAAKTLGIVMGVFILCWLP 210

                         90
                 ....*....|.
gi 347453047  81 LSIINFVSYFQ 91
Cdd:cd15067  211 FFVTNILIGFC 221