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 633257730   1 MFGWNNLSEVEQAWIANGSVGEPVIKCEFEKVISMEYMVYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDP 80
Cdd:cd15071  134 MFGWNNLNAVERAWAANSSMGELVIKCQFETVISMEYMVYFNFFVWVLPPLLLMLLIYLEVFYLIRKQLNKKVSSSSSDP 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730  81 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15071  214 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPSCKKPMILTYIAIFLTHGNSAMNPIVYAFRIKKFRTTF 290

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 633257730   1 MFGWNNLSEVEQAWIANGSVGEPVIKCEFEKVISMEYMVYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDP 80
Cdd:cd15071  134 MFGWNNLNAVERAWAANSSMGELVIKCQFETVISMEYMVYFNFFVWVLPPLLLMLLIYLEVFYLIRKQLNKKVSSSSSDP 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730  81 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15071  214 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPSCKKPMILTYIAIFLTHGNSAMNPIVYAFRIKKFRTTF 290

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 633257730   1 MFGWNNLSEVEQAWIANGSVGEPVIKCEFEKVISMEYMVYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDP 80
Cdd:cd15071  134 MFGWNNLNAVERAWAANSSMGELVIKCQFETVISMEYMVYFNFFVWVLPPLLLMLLIYLEVFYLIRKQLNKKVSSSSSDP 213

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730  81 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15071  214 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPSCKKPMILTYIAIFLTHGNSAMNPIVYAFRIKKFRTTF 290

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 633257730   1 MFGWNNLSEVEqawiangSVGEPVIKCEFEKVISMEYMVYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKKVSASSgDP 80
Cdd:cd15070  134 MFGWNRKPSLE-------SVNTTPLQCQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFR-ET 205

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730  81 QKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPtcQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15070  206 GAFYGREFKTAKSLALVLFLFAVCWLPLSIINCVVYFNP--KVPKIALYLGILLSHANSMMNPIVYACKIKKFKETY 280

adenosine receptor subtype 2AB, member of the class A family of seven-transmembrane G protein-coupled receptors; The A2B 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 633257730   1 MFGWNN----LSEVEQAWIANGSVGEPVIKCEFEKVISMEYMVYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKkvSAS 76
Cdd:cd15069  134 FLGWNKamsaTNNSTNPADHGTNHSCCLISCLFENVVPMSYMVYFNFFGCVLPPLLIMLVIYIKIFLVACRQLQR--TEL 211

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  77 SGDPQKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTC--QKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFR 154
Cdd:cd15069  212 MDHSRTTLQREIHAAKSLAIIVGIFALCWLPVHILNCITLFQPEFskSKPKWAMNVAILLSHANSVVNPIVYAYRNRDFR 291

                 ...
gi 633257730 155 VTF 157
Cdd:cd15069  292 YTF 294

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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730 104 SWLPLHILNCITLFCPTCQKPSILIYI---AIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15095  232 CWLPNHVLNLWQRFDPNFPETYATYALkiaALCLSYANSAVNPFVYAFMGENFRKYF 288

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
                 ....*....|....*....|....*....|....*....|....*..
gi 633257730 104 SWLPLHILNCITLFCPT-CQKPSILIYIAIFLTHGNSAMNPIVYAFR 149
Cdd:cd00637  228 CWLPYFILLLLDVFGPDpSPLPRILYFLALLLAYLNSAINPIIYAFF 274

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
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 633257730 104 SWLPLHILNCITLFCPTCQKPSILIYIAIF-----LTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd14993  238 SWLPYYVLSILLDFGPLSSEESDENFLLILpfaqlLGYSNSAINPIIYCFMSKKFRRGF 296

D1-like family of dopamine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Dopamine receptors are members of the class A G protein-coupled receptors that are involved in many neurological processes in the central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous agonist for dopamine receptors. Dopamine receptors consist of at least five subtypes: D1, D2, D3, D4, and D5. The D1 and D5 subtypes are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 subtypes are members of the D2-like family. The D1-like family receptors are coupled to G proteins of the G(s) family, which activate adenylate cyclase, causing cAMP formation and activation of protein kinase A. In contrast, activation of D2-like family receptors is linked to G proteins of the G(i) family, which inhibit adenylate cyclase. Dopamine receptors are major therapeutic targets for neurological and psychiatric disorders such as drug abuse, depression, schizophrenia, or Parkinson's disease. 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 633257730  57 IYLEVFYLIRKQ------LNKKVSASSGDPQKYYG---KELKIAKSLALILFLFALSWLPLHILNCITLFC------PTC 121
Cdd:cd15057  186 TYTRIYRIARRQirriaaLERAAQESTNPDSSLRSslrRETKALKTLSIIMGVFVCCWLPFFILNCVLPFCdlrtaqFPC 265

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 633257730 122 QKPSILIyIAIFLTHGNSAMNPIVYAFRiHKFRVTF 157
Cdd:cd15057  266 VPDTTFI-VFVWLGWANSSLNPIIYAFN-ADFRKAF 299

somatostatin receptor type 3, member of the class A family of seven-transmembrane G protein-coupled receptors; G protein-coupled somatostatin receptors (SSTRs) are composed of five distinct subtypes (SSTR1-5) that display strong sequence similarity with opioid receptors. All five receptor subtypes bind the natural somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. SSTR3 is coupled to inward rectifying potassium channels. SSTR3 plays critical roles in growth hormone secretion, endothelial cell cycle arrest and apoptosis. Furthermore, SSTR3 is expressed in the normal human pituitary and in nearly half of pituitary growth hormone adenomas.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  71 KKVSASsgdPQKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSI--LIYIAIFLTHGNSAMNPIVYAF 148
Cdd:cd15972  194 RRVRAT---STKRRGSERKVTRMVVIVVAAFVLCWLPFYALNIVNLVCPLPEEPSLfgLYFFVVVLSYANSCANPIIYGF 270

                 ....*....
gi 633257730 149 RIHKFRVTF 157
Cdd:cd15972  271 LSDNFKQGF 279

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 633257730 104 SWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15064  205 CWLPFFLVALIVPLCSHCWIPLALKSFFLWLGYFNSLINPLIYTFFNKDFRKAF 258

D1A (or D1) subtype dopamine receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Dopamine receptors are members of the class A G protein-coupled receptors that are involved in many neurological processes in the central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous agonist for dopamine receptors. Dopamine receptors consist of at least five subtypes: D1, D2, D3, D4, and D5. The D1 and D5 subtypes are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 subtypes are members of the D2-like family. The D1-like family receptors are coupled to G proteins of the G(s) family, which activate adenylate cyclase, causing cAMP formation and activation of protein kinase A. Dopamine receptors are major therapeutic targets for neurological and psychiatric disorders such as drug abuse, depression, schizophrenia, or Parkinson's disease.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 633257730  84 YGKELKIAKSLALILFLFALSWLPLHILNCITLFC-PTCQKP----SILIYIAIFLTHGNSAMNPIVYAFRIhKFRVTF 157
Cdd:cd15320  242 FKRETKVLKTLSVIMGVFVCCWLPFFILNCMVPFCkPTSTEPfcisSTTFDVFVWFGWANSSLNPIIYAFNA-DFRKAF 319

trace amine-associated receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The trace amine-associated receptors (TAARs) are 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 633257730  57 IYLEVFYLIRKQ------LNKKVSA---SSGDPQKyygKELKIAKSLALILFLFALSWLPLHilnCITLFCPTCQKPSIL 127
Cdd:cd15055  182 LYMRIFVVARSQarairsHTAQVSLegsSKKVSKK---SERKAAKTLGIVVGVFLLCWLPYY---IVSLVDPYISTPSSV 255

                         90       100
                 ....*....|....*....|.
gi 633257730 128 IYIAIFLTHGNSAMNPIVYAF 148
Cdd:cd15055  256 FDVLIWLGYFNSCLNPLIYAL 276

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 633257730  57 IYLEVFYLIRKQ---LNKKVSASSGDPQKyygKELKIAKSLALILFLFALSWLPLHILNCITLFCPtCQKPSILIYIAIF 133
Cdd:cd15314  183 IYLKIFLVAQRQarsIQSARTKSGASSSK---MERKATKTLAIVMGVFLLCWTPFFLCNIIDPFIN-YSIPPVLIEVLNW 258

                         90       100
                 ....*....|....*....|....
gi 633257730 134 LTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15314  259 LGYSNSTLNPFIYAFFYSWFRKAF 282

histamine subtype H1 receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes histamine receptor subtype H1R, 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). H1R selectively interacts with the G(q)-type G protein that activates phospholipase C and the phosphatidylinositol pathway. Antihistamines, a widely used anti-allergy medication, act on the H1 subtype and produce drowsiness as a side effect. 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 633257730  86 KELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSiLIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15050  193 RERKAAKQLGFIMAAFILCWIPYFILFMVIAFCKNCCNEN-LHMFTIWLGYINSTLNPFIYPLCNENFKKTF 263

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
                 ....*....|....*....|....*....|....*....|....*....|...
gi 633257730 105 WLPLHILNCITLFCPtCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15061  205 WLPFFIMYLIEPFCD-CQFSEALSTAFTWLGYFNSVINPFIYAFYNKDFRRAF 256

muscarinic acetylcholine receptor subtype M3, 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. The M3 receptor is mainly located in smooth muscle, exocrine glands and vascular endothelium. It induces vomiting in the central nervous system and is a critical regulator of glucose homeostasis by modulating insulin secretion. Generally, M3 receptor causes contraction of smooth muscle resulting in vasoconstriction and increased glandular 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 633257730  86 KELKIAKSLALILFLFALSWLPLHILNCITLFCPTCqKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15299  195 KEKKAAQTLSAILLAFIITWTPYNIMVLVNTFCDSC-IPKTYWNLGYWLCYINSTVNPVCYALCNKTFRTTF 265

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 633257730  87 ELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPsILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15063  197 ETKAAKTVAIIVGCFIFCWLPFFTVYLVRAFCEDCIPP-LLFSVFFWLGYCNSALNPCIYALFSRDFRFAF 266

tyramine/octopamine receptor-like, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes tyramine/octopamine receptors and similar proteins found in insects and other 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 633257730  86 KELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15060  189 KERRAARTLGIIMGVFVVCWLPFFLMYVILPFCETCSPSAKVVNFITWLGYVNSALNPVIYTIFNLDFRRAF 260

muscarinic acetylcholine receptor GAR-2 and similar proteins, 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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 633257730 105 WLPLHILNCITLFC--PTCQkPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15302  213 WTPYHILATIYGFCeaPPCV-NETLYTISYYLCYMNSPINPFCYALANQQFKKTF 266

D1B (or D5) subtype dopamine receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Dopamine receptors are members of the class A G protein-coupled receptors that are involved in many neurological processes in the central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous agonist for dopamine receptors. Dopamine receptors consist of at least five subtypes: D1, D2, D3, D4, and D5. The D1 and D5 subtypes are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 subtypes are members of the D2-like family. The D1-like family receptors are coupled to G proteins of the G(s) family, which activate adenylate cyclase, causing cAMP formation and activation of protein kinase A. Dopamine receptors are major therapeutic targets for neurological and psychiatric disorders such as drug abuse, depression, schizophrenia, or Parkinson's disease.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  86 KELKIAKSLALILFLFALSWLPLHILNCITLFC--PTCQKPSILIYIA-----IFLTHG--NSAMNPIVYAFRIhKFRVT 156
Cdd:cd15319  238 KETKVLKTLSVIMGVFVCCWLPFFILNCMVPFCdrPPADPDAGLPCVSettfdVFVWFGwaNSSLNPIIYAFNA-DFRKV 316

                 .
gi 633257730 157 F 157
Cdd:cd15319  317 F 317

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 633257730 104 SWLPLHILNCITLF--CPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15098  227 SWLPHHIIHLWVEFgdFPLTQASFVLRITAHCLAYANSCVNPIIYAFLSENFRKAY 282

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 633257730 105 WLPLHILNCITLFC---PTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15329  205 WLPFFILALLRPFLkpiKCSCIPLWLSRLFLWLGYANSFLNPIIYAKFNREFRTPF 260

muscarinic acetylcholine receptor subtype M4, 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 G(i/o) types of G proteins. The M4 receptor is mainly found in the CNS and function as an inhibitory autoreceptor regulating acetycholine release. 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 633257730  85 GKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCqKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15298  191 ARERKVTRTIFAILLAFILTWTPYNVMVLVNTFCQSC-IPDTVWSIGYWLCYVNSTINPACYALCNATFKKTF 262

opioid receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes opioid receptors, somatostatin receptors, melanin-concentrating hormone receptors (MCHRs), and neuropeptides B/W receptors. Together they constitute the opioid receptor-like family, members of the class A G-protein coupled receptors. Opioid receptors are coupled to inhibitory G proteins of the G(i/o) family and are involved in regulating a variety of physiological functions such as pain, addiction, mood, stress, epileptic seizure, and obesity, among many others. G protein-coupled somatostatin receptors (SSTRs), which display strong sequence similarity with opioid receptors, binds somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. MCHR binds melanin concentrating hormone and is presumably involved in the neuronal regulation of food intake. Despite strong homology with somatostatin receptors, MCHR does not appear to bind somatostatin. Neuropeptides B/W receptors are primarily expressed in the CNS and stimulate the cortisol secretion by activating the adenylate cyclase- and the phospholipase C-dependent signaling pathways.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 633257730 105 WLPLHILNCITLFcpTCQKPSILI----YIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd14970  228 WLPFHVFQIVRLL--IDPPETLTVvgvfLFCIALSYANSCLNPILYAFLDENFRKSF 282

alpha-1 adrenergic receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; The alpha-1 adrenergic receptors (or adrenoceptors) are a subfamily of the class A rhodopsin-like GPCRs that share a common architecture of seven transmembrane helices. This subfamily consists of three highly homologous receptor subtypes that primarily mediate smooth muscle contraction: alpha-1A, alpha-1B, and alpha-1D. Activation of alpha-1 receptors by catecholamines such as norepinephrine and epinephrine couples to the G(q) protein, which then activates the phospholipase C pathway, leading to an increase in IP3 and calcium. Consequently, the elevation of intracellular calcium concentration leads to vasoconstriction in smooth muscle of blood vessels. In addition, activation of alpha-1 receptors by phenylpropanolamine (PPA) produces anorexia and may induce appetite suppression in rats.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 633257730  84 YGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15062  188 FSREKKAAKTLGIVVGAFVLCWFPFFVVLPLGSLFSTLKPPEPVFKVVFWLGYFNSCLNPIIYPCSSREFKRAF 261

melanocortin receptor subtype 2, also called adrenocorticotropic hormone receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; The melanocortin receptor (MCR) subfamily is a member of the class A family of seven-transmembrane G-protein coupled receptors. MCRs bind a group of pituitary peptide hormones known as melanocortins, which include adrenocorticotropic hormone (ACTH) and the different isoforms of melanocyte-stimulating hormones. There are five known subtypes of the MCR subfamily. MC1R is involved in regulating skin pigmentation and hair color. ACTH (adrenocorticotropic hormone) is the only endogenous ligand for MC2R, which shows low sequence similarity with other melanocortin receptors. Mutations in MC2R cause familial glucocorticoid deficiency type 1, in which patients have elevated plasma ACTH and low cortisol levels. MC3R is expressed in many parts of the brain and peripheral tissues and involved in the regulation of energy homeostasis. MC4R is expressed primarily in the central nervous system and involved in both eating behavior and sexual function. MC5R is widely expressed in peripheral tissues and is mainly involved in the regulation of exocrine gland function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  57 IYLEVFYLIRKQlNKKVSASSGDPQKYYGKELKIAKSLALILFLFALSWLP--LHILncITLFCPtcQKPSILIYIAIFL 134
Cdd:cd15350  168 LYVHMFLLARSH-ARKIASLPNHHAQHQRSNMRGAITLTILLGVFVCCWAPfvLHLL--LMMFCP--MNPYCACYRSLFQ 242

                         90       100
                 ....*....|....*....|....*...
gi 633257730 135 THG-----NSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15350  243 VNGtlimsHAVIDPAIYAFRSPELRNTF 270

trace amine-associated receptor 5, member of the class A family of seven-transmembrane G protein-coupled receptors; The trace amine-associated receptor 5 is one of the 15 identified amine-activated G protein-coupled receptors (TAARs), a distinct subfamily within the class A G protein-coupled receptors. 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 633257730  57 IYLEVFYLIRKQlNKKVSASSGDPQKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCPTCqKPSILIYIAIFLTH 136
Cdd:cd15318  184 LYVKIFIVAKRQ-ARAIASLLSDTNGASKRERKAAKTLGIAVGVYLLCWLPFTIDTMVDSLLNFI-TPPLLFDIIIWFAY 261

                         90
                 ....*....|....*...
gi 633257730 137 GNSAMNPIVYAFRIHKFR 154
Cdd:cd15318  262 FNSACNPLIYVFSYPWFR 279

sphingosine-1-phosphate receptor subtype 4 (S1PR4 or S1P4), also called endothelial differentiation gene 6 (Edg6), member of the class A family of seven-transmembrane G protein-coupled receptors; The endothelial differentiation gene (Edg) family of G-protein coupled receptors binds blood borne lysophospholipids including sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which are involved in the regulation of cell proliferation, survival, migration, invasion, endothelial cell shape change and cytoskeletal remodeling. The Edg receptors are classified into two subfamilies: the lysophosphatidic acid subfamily that includes LPA1 (Edg2), LPA2 (Edg4), and LPA3 (Edg7); and the S1P subfamily that includes S1P1 (Edg1), S1P2 (Edg5), S1P3 (Edg3), S1P4 (Edg6), and S1P5 (Edg8). The Edg receptors couple and activate at least three different G protein subtypes including G(i/o), G(q/11), and G(12/13).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  57 IYLEVFYLIRKQLNKKVSASSGDpqkyygKELKIAKSLALILFLFALSWLPLHILNCITLFC--PTCQKPSILIYIaIFL 134
Cdd:cd15349  176 LYFAIYCLVRASGQRVISARSRR------RSLRLLKTVLMILGAFMVCWGPLFILLLVDFFCssRSCKPLFGMEWV-LAL 248

                         90       100
                 ....*....|....*....|
gi 633257730 135 THGNSAMNPIVYAFRIHKFR 154
Cdd:cd15349  249 AVLNSAINPLIYSFRSLEVR 268

lysophosphatidic acid receptor subtype 2 (LPAR2 or LPA2), also called Endothelial differentiation gene 4 (Edg4), member of the class A family of seven-transmembrane G protein-coupled receptors; The endothelial differentiation gene (Edg) family of G-protein coupled receptors binds blood borne lysophospholipids including sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which are involved in the regulation of cell proliferation, survival, migration, invasion, endothelial cell shape change and cytoskeletal remodeling. The Edg receptors are classified into two subfamilies: the lysophosphatidic acid subfamily that includes LPA1 (Edg2), LPA2 (Edg4), and LPA3 (Edg7); and the S1P subfamily that includes S1P1 (Edg1), S1P2 (Edg5), S1P3 (Edg3), S1P4 (Edg6), and S1P5 (Edg8). The Edg receptors couple and activate at least three different G protein subtypes including G(i/o), G(q/11), and G(12/13).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  57 IYLEVFYLIRKQLnKKVSASSGDPQKYYGKELKIAKSLALILFLFALSWLP-LHILNCITLFCPTCQKPSILIYIaIFLT 135
Cdd:cd15342  175 VYTRIFIYVRRKS-QRMSEHHSSHPRYRETVLGLMKTVVIILGAFVVCWTPgQVVLLLDGLGCESCNVLAYEKYF-LLLA 252

                         90       100
                 ....*....|....*....|..
gi 633257730 136 HGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15342  253 EINSLVNPIVYSYRDKEMRKTF 274

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 633257730 105 WLPLHILNCITLFCPTCQKPSI--LIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15974  223 WLPFYMLNIVNLIVILPEEPAFvgVYFFVVVLSYANSCANPILYGFLSDNFKQSF 277

trace amine-associated receptors 6, 8, and 9, member of the class A family of seven-transmembrane G protein-coupled receptors; Included in this group are mammalian TAAR6, TAAR8, TAAR9, and similar proteins. They are among the 15 identified amine-associated receptors (TAARs), a distinct subfamily within the class A G protein-coupled receptors. 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 633257730  57 IYLEVFYLIRKQLNK------KVSASSGDPQKYYGK-ELKIAKSLALILFLFALSWLPLHILNCITLFCPTCQKPsiLIY 129
Cdd:cd15316  184 LYGKIFLVAKQQARKiemtssKAESSSESYKDRVARrERKAAKTLGITVIAFLVSWLPYLIDVLIDAFMNFITPP--YIY 261

                         90       100
                 ....*....|....*....|....*.
gi 633257730 130 -IAIFLTHGNSAMNPIVYAFRIHKFR 154
Cdd:cd15316  262 eICCWCAYYNSAMNPLIYALFYPWFR 287

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 633257730 105 WLPLHILNCI----TLFCPTCQKPSILIYIA-IFLTHGNSAMNPIVYAFRIHKFRV 155
Cdd:cd15391  232 WLPLHLFNLVqdfsTVFRNMPQHTTRLIYGAcHWIAMSNSFVNPIIYLFMNDSFRS 287

lysophosphatidic acid receptor subfamily, member of the class A family of seven-transmembrane G protein-coupled receptors; The endothelial differentiation gene (Edg) family of G-protein coupled receptors binds blood borne lysophospholipids including sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which are involved in the regulation of cell proliferation, survival, migration, invasion, endothelial cell shape change and cytoskeletal remodeling. The Edg receptors are classified into two subfamilies: the lysophosphatidic acid subfamily that includes LPA1 (Edg2), LPA2 (Edg4), and LPA3 (Edg7); and the S1P subfamily that includes S1P1 (Edg1), S1P2 (Edg5), S1P3 (Edg3), S1P4 (Edg6), and S1P5 (Edg8). The Edg receptors couple and activate at least three different G protein subtypes including G(i/o), G(q/11), and G(12/13).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 633257730  57 IYLEVFYLIRKQLNKKVSASSGDPqKYYGKELKIAKSLALILFLFALSWLPLHILNCITLFCptCQKPSILIYIAIFL-- 134
Cdd:cd15101  175 VYARIFVYVRRRTNRMSPHTSGSI-RNRDTMMSLLKTVVIVLGAFVVCWTPGLVVLLLDGLC--CRQCNVLAVEKFFLll 251

                         90       100
                 ....*....|....*....|...
gi 633257730 135 THGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd15101  252 AEFNSAVNPIIYSYRDKEMSGTF 274

histamine receptor subtype H4R, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes histamine subtype H4R, a member of the histamine receptor family, which belong 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 H3 and H4 receptors couple to the G(i)-proteins, which leading to the inhibition of cAMP formation. The H3R receptor functions as a presynaptic autoreceptors controlling histamine release and synthesis. The H4R plays an important role in histamine-mediated chemotaxis in mast cells and eosinophils. 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 633257730  89 KIAKSLALILFLFALSWLPLHILNCITLFCPTcQKPSILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTFLKI 160
Cdd:cd15295  195 KLAKSLAIILGTFAICWAPYSLFTIIRAACEK-HRGSPWYNFAFWLQWFNSFINPFLYPLCHKRFRKAFLKI 265

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 633257730 104 SWLPLHILNCITLFCPTCQKPS--ILIYIAIFLTHGNSAMNPIVYAFRIHKFRVTF 157
Cdd:cd14971  226 CWGPIHAILLLVALGPFPLTYAtyALRIWAHCLAYSNSAVNPVLYAFLSEHFRKAF 281