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 296024869   29 YMVYVSFFAGILLPLVVMCGIYLDIFYVIRNKLSQNFSSSKEtsafyGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYF 108
Cdd:pfam00001 150 SYTLLISVLGFLLPLLVILVCYTLIIRTLRKSASKQKSSERT-----QRRRKALKTLAVVVVVFILCWLPYHIVNLLDSL 224

                          90       100
                  ....*....|....*....|....*
gi 296024869  109 SGEVP-----PVVLYLGILLSHANS 128
Cdd:pfam00001 225 ALDCElsrllDKALSVTLWLAYVNS 249

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296024869   1 GWNMKMTPGHHINATFLSCQFRSVIRMDYMVYVSFFAGILLPLVVMCGIYLDIFYVIRNKLSQNFS--SSKETSAFYGRE 78
Cdd:cd14968  136 GWNNGAPLESGCGEGGIQCLFEEVIPMDYMVYFNFFACVLVPLLIMLVIYLRIFRVIRKQLRQIESllRSRRSRSTLQKE 215

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 296024869  79 FKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGE--VPPVVLYLGILLSHANS 128
Cdd:cd14968  216 VKAAKSLAIILFLFALCWLPLHIINCITLFCPEckVPKILTYIAILLSHANS 267

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 296024869   1 GWNMKMTP-GHHINAT-----FLSCQFRSVIRMDYMVYVSFFAGILLPLVVMCGIYLDIFYVIRNKLSQNFSSS---KET 71
Cdd:cd15068  136 GWNNCGQPkEGKNHSQgcgegQVACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPlpgERA 215

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 296024869  72 SAFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEV---PPVVLYLGILLSHANS 128
Cdd:cd15068  216 RSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCPDCshaPLWLMYLAIVLSHTNS 275

rhodopsin receptor-like class A family of the seven-transmembrane G protein-coupled receptor superfamily; Class A rhodopsin-like receptors constitute about 90% of all GPCRs. The class A GPCRs include the light-sensitive rhodopsin as well as receptors for biogenic amines, lipids, nucleotides, odorants, peptide hormones, and a variety of other ligands. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. Based on sequence similarity, GPCRs can be divided into six major classes: class A (rhodopsin-like family), class B (Methuselah-like, adhesion and secretin-like receptor family), class C (metabotropic glutamate receptor family), class D (fungal mating pheromone receptors), class E (cAMP receptor family), and class F (frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296024869  10 HHINATFLSCQFRSVIRMDYMVYVsFFAGILLPLVVMCGIYLDIFYVIR--NKLSQNFSSSKETSAFYGREFKTAKSLSL 87
Cdd:cd00637  142 YGGYCCCCLCWPDLTLSKAYTIFL-FVLLFLLPLLVIIVCYVRIFRKLRrhRRRIRSSSSNSSRRRRRRRERKVTKTLLI 220

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 296024869  88 VLLLFAVSWLPLSIMNCVIYFSGE---VPPVVLYLGILLSHANS 128
Cdd:cd00637  221 VVVVFLLCWLPYFILLLLDVFGPDpspLPRILYFLALLLAYLNS 264

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296024869   1 GWNmkmTPGHHI--NATFLSCQFRsvIRMDYMVYVSFFAgILLPLVVMCGIYLDIFYVIR------NKLSQNFSSSKETS 72
Cdd:cd15051  139 GWN---TPDGRVqnGDTPNQCRFE--LNPPYVLLVAIGT-FYLPLLIMCGVYLRIFRIAReqakriNALTPASTANSSKS 212

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 296024869  73 AFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEVPPVVLYLGIL-LSHANS 128
Cdd:cd15051  213 AATAREHKATVTLAAVLGAFIICWFPYFTYFTYRGLCGDNINETALSVVLwLGYANS 269

muscarinic acetylcholine receptor subfamily, member of the class A family of seven-transmembrane G protein-coupled receptors; Muscarinic acetylcholine receptors (mAChRs) regulate the activity of many fundamental central and peripheral functions. The mAChR family consists of 5 subtypes M1-M5, which can be further divided into two major groups according to their G-protein coupling preference. The M1, M3 and M5 receptors selectively interact with G proteins of the G(q/11) family, whereas the M2 and M4 receptors preferentially link to the G(i/o) types of G proteins. Activation of mAChRs by agonist (acetylcholine) leads to a variety of biochemical and electrophysiological responses. In general, the exact nature of these responses and the subsequent physiological effects mainly depend on the molecular and pharmacological identity of the activated receptor subtype(s). 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 296024869  29 YMVYVSFFAGILLPLVVMCGIYLDIFyvirnklsqnfsssKETSafygREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYF 108
Cdd:cd15049  162 AITFGTAIAAFYLPVLVMTILYWRIY--------------RETA----RERKAARTLSAILLAFIITWTPYNILVLVSTF 223

                         90       100
                 ....*....|....*....|.
gi 296024869 109 SGEVPPVVLY-LGILLSHANS 128
Cdd:cd15049  224 CAKCIPDTLWsFGYWLCYINS 244

trace amine-associated receptors 2, 3, 4, and similar receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; TAAR2, TAAR3, and TAAR4 are among 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. Trace amines, including p-tyramine, beta-phenylethylamine, and tryptamine, are also thought to act as chemical messengers to exert their biological effects in vertebrates. 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 296024869  33 VSFFAGILLPLVVMCGIYLDIFYVIR------NKLSQNFSSSKETSAFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVI 106
Cdd:cd15312  169 IASLIAFFIPGTVMIGIYIKIFFVARkhakviNNRPSVTKGDSKNKLSKKKERKAAKTLSIVMGVFLLCWLPFFVATLID 248

                         90
                 ....*....|..
gi 296024869 107 YFSGEVPPVVLY 118
Cdd:cd15312  249 PFLNFSTPVDLF 260

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 296024869  40 LLPLVVMCGIYLDIFYV--IRNKLSQNFSSSKETSAFYGRE-FKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEVP--- 113
Cdd:cd14993  180 VLPLLIISVAYSLIGRRlwRRKPPGDRGSANSTSSRRILRSkKKVARMLIVVVVLFALSWLPYYVLSILLDFGPLSSees 259

                         90
                 ....*....|....*....
gi 296024869 114 ----PVVLYLGILLSHANS 128
Cdd:cd14993  260 denfLLILPFAQLLGYSNS 278

muscarinic acetylcholine receptor subtype M1, member of the class A family of seven-transmembrane G protein-coupled receptors; Muscarinic acetylcholine receptors (mAChRs) regulate the activity of many fundamental central and peripheral functions. The mAChR family consists of 5 subtypes M1-M5, which can be further divided into two major groups according to their G-protein coupling preference. The M1, M3 and M5 receptors selectively interact with G proteins of the G(q/11) family, whereas the M2 and M4 receptors preferentially link to the G(i/o) types of G proteins. Activation of mAChRs by agonist (acetylcholine) leads to a variety of biochemical and electrophysiological responses. M1 is the dominant mAChR subtype involved in learning and memory. It is linked to synaptic plasticity, neuronal excitability, and neuronal differentiation during early development. 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 296024869  37 AGILLPLVVMCGIYLDIFyvirnklsqnfsssKETSafygREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEVPPVV 116
Cdd:cd17790  170 AAFYLPVTIMIILYWRIY--------------RETI----KEKKAARTLSAILLAFILTWTPYNIMVLVSTFCKDCVPKT 231

                         90
                 ....*....|...
gi 296024869 117 LY-LGILLSHANS 128
Cdd:cd17790  232 LWeLGYWLCYVNS 244

galanin receptor subtype 1, 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 296024869  27 MDYMVYV--SFFAGILLPLVVMCGIYLDIFYVIrNKLSQNFSSSKETSafygrEFKTAKSLSLVLLLFAVSWLPLSIMNC 104
Cdd:cd15098  163 QQKPVYVvcTFVFGYLLPLLLITFCYAKVLNHL-HKKLKNMSKKSERS-----KKKTAQTVLVVVVVFGISWLPHHIIHL 236

                         90       100
                 ....*....|....*....|....*....
gi 296024869 105 VIYFsGEVPP-----VVLYLGILLSHANS 128
Cdd:cd15098  237 WVEF-GDFPLtqasfVLRITAHCLAYANS 264

tyramine receptors and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes tyramine-specific receptors and similar proteins found in insects and other invertebrates. These tyramine receptors form a distinct receptor family that is phylogenetically different from the other tyramine/octopamine receptors which also found in invertebrates. Both octopamine and tyramine mediate their actions via G protein-coupled receptors (GPCRs) and are the invertebrate equivalent of vertebrate adrenergic neurotransmitters. In Drosophila, octopamine is involved in ovulation by mediating an egg release from the ovary, while a physiological role for tyramine in this process is not fully understood. 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 296024869   8 PGHHINATFLSCQFRSviRMDYMVYvSFFAGILLPLVVMCGIYLDIFYVIRnklsqnfsssketsafygREFKTAKSLSL 87
Cdd:cd15061  138 PSWHGRRGLGSCYYTY--DKGYRIY-SSMGSFFLPLLLMLFVYLRIFRVIA------------------KERKTAKTLAI 196

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 296024869  88 VLLLFAVSWLPLSIMN-----CVIYFSGEVPPVVLYLGILLSHAN 127
Cdd:cd15061  197 VVGCFIVCWLPFFIMYliepfCDCQFSEALSTAFTWLGYFNSVIN 241

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 296024869  40 LLPLVVMCGIYLDIFYVIRN----KLSQNFSSSKETSAFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEVPPV 115
Cdd:cd15203  177 VIPLLIISFCYFRISLKLRKrvkkKRGKRTLSSRRRRSELRRKRRTNRLLIAMVVVFAVCWLPLNLFNLLRDFEPLPQID 256

neuropeptide Y receptor type 2, 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 296024869  40 LLPLVVMCGIYLDIFyvirNKLSQNFSSSKETSAFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEV 112
Cdd:cd15399  178 VLPLAIISYAYIRIW----TKLKNHVSPGGGNDHYHQRRRKTTKMLVCVVVVFAVSWLPFHAFQLASDIDSKV 246

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 296024869  33 VSFFAGILLPLVVMCGIYLDIFYVI--------------RNKLSQNFSSSKETSAFYGREfKTAKSLSLVLLLFAVSWLP 98
Cdd:cd15208  171 CFFLVTYLLPLCLMILAYFQIFRKLwcrqipgtssvvqrKWNKPRKSAVAAEEKQLRSRR-KTAKMLIVVVIMFAICYLP 249

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 296024869  99 LSIMNCVIYFSG--EVPPVVLYLGILLSH----ANS 128
Cdd:cd15208  250 VHLLNILRYVFGlfTVDRETIYAWFLFSHwlvyANS 285

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 296024869  40 LLPLVVMCGIYLDIFYVIRNK--LSQNFSSSKETSAFYGREFKTAKSLSLVLLLFAVSWLPLSIMNCVIYF 108
Cdd:cd15207  176 VAPLLIIAVLYVRIGYRLWFKpvPGGGSASREAQAAVSKKKVRVIKMLIVVVVLFALSWLPLHTVTMLDDF 246

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 296024869  29 YMVYvSFFAGILLPLVVMCGIYLDIFYVIRNKLSQNFSSSKETSafygrEFKTAKSLSLVLLLFAVSWLPLSIMNcVIYF 108
Cdd:cd15971  164 FIIY-TFILGFFVPLTIICLCYLFIIIKVKSSGIRVGSSKRKKS-----EKKVTRMVSIVVAVFVFCWLPFYIFN-VSSV 236

                         90       100
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gi 296024869 109 SGEVPPVVLYLG-----ILLSHANS 128
Cdd:cd15971  237 SVSISPTPGLKGmfdfvVVLSYANS 261

muscarinic acetylcholine receptor subtype M5, member of the class A family of seven-transmembrane G protein-coupled receptors; Muscarinic acetylcholine receptors (mAChRs) regulate the activity of many fundamental central and peripheral functions. The mAChR family consists of 5 subtypes M1-M5, which can be further divided into two major groups according to their G-protein coupling preference. The M1, M3 and M5 receptors selectively interact with G proteins of the G(q/11) family, whereas the M2 and M4 receptors preferentially link to the G(i/o) types of G proteins. M5 mAChR is primarily found in the central nervous system and mediates acetylcholine-induced dilation of cerebral blood vessels. Activation of M5 receptor triggers a variety of cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides, and modulation of potassium channels. 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 296024869  77 REFKTAKSLSLVLLLFAVSWLPLSIMNCVIYFSGEVPPVVLY-LGILLSHANS 128
Cdd:cd15300  192 KERKAAQTLSAILLAFIITWTPYNIMVLVSTFCSDCIPLTLWhLGYWLCYVNS 244