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 168831196   5 PGYHRNATFFSCQFRSVIRMDYMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQNFSSSKETSAFYGREFKTAKSLSL 84
Cdd:cd15070  142 SLESVNTTPLQCQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLAL 221

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 168831196  85 VLFLFAVSWLPLSIMNCVIYFGGEVPQVVLYLGILLSHA 123
Cdd:cd15070  222 VLFLFAVCWLPLSIINCVVYFNPKVPKIALYLGILLSHA 260

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 168831196   5 PGYHRNATFFSCQFRSVIRMDYMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQNFSSSKETSAFYGREFKTAKSLSL 84
Cdd:cd15070  142 SLESVNTTPLQCQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLAL 221

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 168831196  85 VLFLFAVSWLPLSIMNCVIYFGGEVPQVVLYLGILLSHA 123
Cdd:cd15070  222 VLFLFAVCWLPLSIINCVVYFNPKVPKIALYLGILLSHA 260

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 168831196   5 PGYHRNATFFSCQFRSVIRMDYMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQNFSSSKETSAFYGREFKTAKSLSL 84
Cdd:cd15070  142 SLESVNTTPLQCQFTSVMRMDYMVYFSFFTWILIPLVIMCALYVDIFYIIRNKLSQNATGFRETGAFYGREFKTAKSLAL 221

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 168831196  85 VLFLFAVSWLPLSIMNCVIYFGGEVPQVVLYLGILLSHA 123
Cdd:cd15070  222 VLFLFAVCWLPLSIINCVVYFNPKVPKIALYLGILLSHA 260

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 168831196  15 SCQFRSVIRMDYMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQNFSS-SKETSAFYGREFKTAKSLSLVLFLFAVSW 93
Cdd:cd15071  159 KCQFETVISMEYMVYFNFFVWVLPPLLLMLLIYLEVFYLIRKQLNKKVSSsSSDPQKYYGKELKIAKSLALILFLFALSW 238

                         90       100       110
                 ....*....|....*....|....*....|.
gi 168831196  94 LPLSIMNCVIYF--GGEVPQVVLYLGILLSH 122
Cdd:cd15071  239 LPLHILNCITLFcpSCKKPMILTYIAIFLTH 269

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 168831196  13 FFSCQFRSVIRMDYMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQN--FSSSKETsafYGREFKTAKSLSLVLFLFA 90
Cdd:cd15069  161 LISCLFENVVPMSYMVYFNFFGCVLPPLLIMLVIYIKIFLVACRQLQRTelMDHSRTT---LQREIHAAKSLAIIVGIFA 237

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 168831196  91 VSWLPLSIMNCVIYF----GGEVPQVVLYLGILLSHA 123
Cdd:cd15069  238 LCWLPVHILNCITLFqpefSKSKPKWAMNVAILLSHA 274

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 168831196   26 YMVYLSFFTGILIPLVVMCVIYLDIFYIIRNKLSQNFSSSKEtsafyGREFKTAKSLSLVLFLFAVSWLPLSIMNCVIYF 105
Cdd:pfam00001 150 SYTLLISVLGFLLPLLVILVCYTLIIRTLRKSASKQKSSERT-----QRRRKALKTLAVVVVVFILCWLPYHIVNLLDSL 224

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 168831196  30 LSFFtgilIPLVVMCVIYLDIFYIIRNKL------------SQNFSSSKETSAFygREFKTAKSLSLVLFLFAVSWLPLS 97
Cdd:cd15057  174 ISFY----IPVAIMIVTYTRIYRIARRQIrriaaleraaqeSTNPDSSLRSSLR--RETKALKTLSIIMGVFVCCWLPFF 247

                 ....*...
gi 168831196  98 IMNCVIYF 105
Cdd:cd15057  248 ILNCVLPF 255

vertebrate melanopsins and related opsins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group represent the Gq-coupled rhodopsin subfamily consists of melanopsins, insect photoreceptors R1-R6, invertebrate Gq opsins as well as their closely related opsins. Melanopsins (also called Opsin-4) are the primary photoreceptor molecules for non-visual functions such as the photo-entrainment of the circadian rhythm and pupillary constriction in mammals. Mammalian melanopsins are expressed only in the inner retina, whereas non-mammalian vertebrate melanopsins are localized in various extra-retinal tissues such as iris, brain, pineal gland, and skin. The outer photoreceptors (R1-R6) are the insect Drosophila equivalent to the vertebrate rods and are responsible for image formation and motion detection. The invertebrate G(q) opsins includes the arthropod and mollusk visual opsins as well as invertebrate melanopsins, which are also found in vertebrates. Arthropods possess color vision by the use of multiple opsins sensitive to different light wavelengths. Members of this subfamily belong to the class A of the G protein-coupled receptors and have seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 168831196  26 YMVYLSFFtGILIPLVVMCVIYLDIFYIIRN----------KLSQNFSSSKETSAfyGREFKTAKSLSLVLFLFAVSWLP 95
Cdd:cd15083  165 YVICLLIF-GFVLPLLIIIYCYSFIFRAVRRhekamkemakRFSKSELSSPKARR--QAEVKTAKIALLLVLLFCLAWTP 241

                         90
                 ....*....|.
gi 168831196  96 LSIMNCVIYFG 106
Cdd:cd15083  242 YAVVALIGQFG 252

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 168831196  38 IPLVVMCVIYLDIFyiirnklsqnfsssKETSafygREFKTAKSLSLVLFLFAVSWLPLSIMNCVIYFGGEVPQVVLY 115
Cdd:cd15049  174 LPVLVMTILYWRIY--------------RETA----RERKAARTLSAILLAFIITWTPYNILVLVSTFCAKCIPDTLW 233

trace amine-associated receptor 5 and similar receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Included in this group are mammalian TAAR5, TAAR6, TAAR8, TAAR9, and similar proteins. They are among the 15 identified trace 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 168831196  27 MVYLSFFtgilIPLVVMCVIYLDIFYIIRNKLSQ--------NFSSSKETSAFYGREFKTAKSLSLVLFLFAVSWLPLSI 98
Cdd:cd15317  169 LDFLTFF----IPCLIMIGLYAKIFLVARRQARKiqnmedkfRSSEENSSKASASRERKAAKTLAIVMGIFLFCWLPYFI 244

                         90
                 ....*....|....*..
gi 168831196  99 MNCVIYFGGEVPQVVLY 115
Cdd:cd15317  245 DTIVDEYSNFITPAIVF 261

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 168831196  37 LIPLVVMCVIYLDIFYIIRNK--LSQNFSSSKETSAFYGREFKTAKSLSLVLFLFAVSWLPLSIMNCVIYFG 106
Cdd:cd15207  176 VAPLLIIAVLYVRIGYRLWFKpvPGGGSASREAQAAVSKKKVRVIKMLIVVVVLFALSWLPLHTVTMLDDFG 247

prolactin-releasing peptide receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Prolactin-releasing peptide (PrRP) receptor (previously known as GPR10) is expressed in the central nervous system with the highest levels located in the anterior pituitary and is activated by its endogenous ligand PrRP, a neuropeptide possessing a C-terminal Arg-Phe-amide motif. There are two active isoforms of PrRP in mammals: one consists of 20 amino acids (PrRP-20) and the other consists of 31 amino acids (PrRP-31), where PrRP-20 is a C-terminal fragment of PrRP-31. Binding of PrRP to the receptor coupled to G(i/o) proteins activates the extracellular signal-related kinase (ERK) and it can also couple to G(q) protein leading to an increase in intracellular calcium and activation of c-Jun N-terminal protein kinase (JNK). The PrRP receptor shares significant sequence homology with the neuropeptide Y (NPY) receptor, and micromolar levels 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. PrRP has been shown to reduce food intake and body weight and modify body temperature when administered in rats. It also has been shown to decrease circulating growth hormone levels by activating somatostatin-secreting neurons in the hypothalamic periventricular nucleus.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 168831196  23 RMDYMVYLSFFTGILiPLVVMCVIYLDIFYIIRNKLSQNFSSSKETSAFYGREFKTAKSLSLVLFLFAVSWLPLSIMN 100
Cdd:cd15394  162 RLAYACSTLLITYVL-PLLAISLSYLRISVKLRNRVVPGSMTQSQAEWDRARRRKTFRLLVVVVVAFAICWLPLHIFN 238

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 168831196  32 FFTGILIPLVVMCVIYLDIF----------YIIRNKLSQNFSSSKETSA----FYGREfKTAKSLSLVLFLFAVSWLPLS 97
Cdd:cd15208  173 FLVTYLLPLCLMILAYFQIFrklwcrqipgTSSVVQRKWNKPRKSAVAAeekqLRSRR-KTAKMLIVVVIMFAICYLPVH 251

                         90
                 ....*....|
gi 168831196  98 IMNCVIYFGG 107
Cdd:cd15208  252 LLNILRYVFG 261

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 168831196  37 LIPLVVMCVIYLDIFYIIRN----KLSQNFSSSKETSAFYGREFKTAKSLSLVLFLFAVSWLPLSIMNCVIYFGGEVPQV 112
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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 168831196  37 LIPLVVMCVIYLDIFyiirNKLSQNFSSSKETSAFYGREFKTAKSLSLVLFLFAVSWLPL 96
Cdd:cd15399  178 VLPLAIISYAYIRIW----TKLKNHVSPGGGNDHYHQRRRKTTKMLVCVVVVFAVSWLPF 233

serotonin receptor subtype 2A, member of the class A family of seven-transmembrane G protein-coupled receptors; The 5-HT2 receptors are a subfamily of serotonin receptors that bind the neurotransmitter serotonin (5HT; 5-hydroxytryptamine) in the central nervous system (CNS). The 5-HT2 subfamily is composed of three subtypes that mediate excitatory neurotransmission: 5-HT2A, 5-HT2B, and 5-HT2C. They are selectively linked to G proteins of the G(q/11) family and activate phospholipase C, which leads to activation of protein kinase C and calcium release. In the CNS, serotonin is involved in the regulation of appetite, mood, sleep, cognition, learning and memory, as well as implicated in diseases such as migraine, schizophrenia, and depression. Indeed, 5-HT2 receptors are attractive targets for a variety of psychoactive drugs, ranging from atypical antipsychotic drugs, antidepressants, and anxiolytics, which have an antagonistic action on 5-HT2 receptors, to hallucinogens, which act as agonists at postsynaptic 5-HT2 receptors. 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 168831196  25 DYMVYLSFFTGILIPLVVMCVIYldifYIIRNKLSQNFSSsketsafygrEFKTAKSLSLVLFLFAVSWLPLSIMNCVIY 104
Cdd:cd15304  158 ENFVLIGSFVAFFIPLTIMVITY----FLTIKSLQQSISN----------EQKASKVLGIVFFLFVVMWCPFFITNVMAV 223

                         90
                 ....*....|....*
gi 168831196 105 FGGEVPQVVLYLGIL 119
Cdd:cd15304  224 ICKESCNEVVIGGLL 238

beta adrenergic receptors (adrenoceptors), member of the class A family of seven-transmembrane G protein-coupled receptors; The beta adrenergic receptor (beta adrenoceptor), also known as beta AR, is activated by hormone adrenaline (epinephrine) and plays important roles in regulating cardiac function and heart rate, as well as pulmonary physiology. The human heart contains three subtypes of the beta AR: beta-1 AR, beta-2 AR, and beta-3 AR. Beta-1 AR and beta-2 AR, which expressed at about a ratio of 70:30, are the major subtypes involved in modulating cardiac contractility and heart rate by positively stimulating the G(s) protein-adenylate cyclase-cAMP-PKA signaling pathway. In contrast, beta-3 AR produces negative inotropic effects by activating inhibitory G(i) proteins. The aberrant expression of beta-ARs can lead to cardiac dysfunction such as arrhythmias or heart failure. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 168831196  16 CQFRSviRMDYMVY---LSFFtgilIPLVVMCVIYLDIFYI-------IRNK--------LSQNFSSSKETSAFYGR--- 74
Cdd:cd15058  158 CDFRT--NMAYAIAssvVSFY----IPLLIMIFVYARVFLIatrqlqlIDKRrlrfqsecPAPQTTSPEGKRSSGRRpsr 231

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 168831196  75 -----EFKTAKSLSLVLFLFAVSWLPLSIMNCVIYFGGEVPQVVLYL 116
Cdd:cd15058  232 ltvvkEHKALKTLGIIMGTFTLCWLPFFIANIINVFNRNLPPGEVFL 278