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 946974170   26 YMVYVSFLTLILIPLVVMCAIYLDIFYVIRNKLSQNFSGSKEagafyGREFKTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:pfam00001 150 SYTLLISVLGFLLPLLVILVCYTLIIRTLRKSASKQKSSERT-----QRRRKALKTLAVVVVVFILCWLPYHIVNLLDSL 224

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 946974170   1 MKLNSGPHRNATFLSCQFRSVMRMDYMVYVSFLTLILIPLVVMCAIYLDIFYVIRNKLSQNFS--GSKEAGAFYGREFKT 78
Cdd:cd14968  139 NGAPLESGCGEGGIQCLFEEVIPMDYMVYFNFFACVLVPLLIMLVIYLRIFRVIRKQLRQIESllRSRRSRSTLQKEVKA 218

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 946974170  79 AKSLSLVLFLFALSWLPLSIINCIIYFDGE--VPEVALYLGILLSHA 123
Cdd:cd14968  219 AKSLAIILFLFALCWLPLHIINCITLFCPEckVPKILTYIAILLSHA 265

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 946974170  14 LSCQFRSVMRMDYMVYVSFLTLILIPLVVMCAIYLDIFYVIRNKLSQNFSGS---KEAGAFYGREFKTAKSLSLVLFLFA 90
Cdd:cd15068  158 VACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPlpgERARSTLQKEVHAAKSLAIIVGLFA 237

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 946974170  91 LSWLPLSIINCIIYFDGEV---PEVALYLGILLSHA 123
Cdd:cd15068  238 LCWLPLHIINCFTFFCPDCshaPLWLMYLAIVLSHT 273

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 946974170   8 HRNATFLSCQFRSVMRMDYMVYVsFLTLILIPLVVMCAIYLDIFYVIR--NKLSQNFSGSKEAGAFYGREFKTAKSLSLV 85
Cdd:cd00637  143 GGYCCCCLCWPDLTLSKAYTIFL-FVLLFLLPLLVIIVCYVRIFRKLRrhRRRIRSSSSNSSRRRRRRRERKVTKTLLIV 221

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 946974170  86 LFLFALSWLPLSIINCIIYFDGEVPEVALYLGILL 120
Cdd:cd00637  222 VVVFLLCWLPYFILLLLDVFGPDPSPLPRILYFLA 256

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 946974170   26 YMVYVSFLTLILIPLVVMCAIYLDIFYVIRNKLSQNFSGSKEagafyGREFKTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:pfam00001 150 SYTLLISVLGFLLPLLVILVCYTLIIRTLRKSASKQKSSERT-----QRRRKALKTLAVVVVVFILCWLPYHIVNLLDSL 224

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 946974170  21 VMRMDYMVYVsFLTLILIPLVVMCAIYLDIFYVIRNKLSQNFSGSKEAGAFYGREF---KTAKSLSLVLFLFALSWLPLS 97
Cdd:cd14993  165 ELRKAYNVAL-FVVLYVLPLLIISVAYSLIGRRLWRRKPPGDRGSANSTSSRRILRskkKVARMLIVVVVLFALSWLPYY 243

                         90
                 ....*....|....*
gi 946974170  98 IINCIIYFDGEVPEV 112
Cdd:cd14993  244 VLSILLDFGPLSSEE 258

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 946974170  28 VYVSFLTLI--LIPLVVMCAIYLDIFYVIRN----------KLSQNFSGSKEAGAfyGREFKTAKSLSLVLFLFALSWLP 95
Cdd:cd15083  164 SYVICLLIFgfVLPLLIIIYCYSFIFRAVRRhekamkemakRFSKSELSSPKARR--QAEVKTAKIALLLVLLFCLAWTP 241

                         90
                 ....*....|
gi 946974170  96 LSIINCIIYF 105
Cdd:cd15083  242 YAVVALIGQF 251

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 946974170  22 MRMDYMVYVSFLTLI--LIPLVVMCAIYLDIFYVIRNKLSQNFSGSKEAGAFYGREFKTAKSLSLVLFLFALSWLPLSII 99
Cdd:cd15394  158 QEKQRLAYACSTLLItyVLPLLAISLSYLRISVKLRNRVVPGSMTQSQAEWDRARRRKTFRLLVVVVVAFAICWLPLHIF 237

                 ...
gi 946974170 100 NCI 102
Cdd:cd15394  238 NVI 240

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 946974170  28 VYVSFLTLiLIPLVVMCAIYLDIFYVIRNKLSQ--------NFSGSKEAGAFYGREFKTAKSLSLVLFLFALSWLPLSI 98
Cdd:cd15317  167 VLLDFLTF-FIPCLIMIGLYAKIFLVARRQARKiqnmedkfRSSEENSSKASASRERKAAKTLAIVMGIFLFCWLPYFI 244

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 946974170  30 VSFLTLILIPLVVMCAIYLDIFYVI--------------RNKLSQNFSGSKEAGAFYGREfKTAKSLSLVLFLFALSWLP 95
Cdd:cd15208  171 CFFLVTYLLPLCLMILAYFQIFRKLwcrqipgtssvvqrKWNKPRKSAVAAEEKQLRSRR-KTAKMLIVVVIMFAICYLP 249

                         90       100
                 ....*....|....*....|....*....
gi 946974170  96 LSIINCIIYFDG--EVPEVALYLGILLSH 122
Cdd:cd15208  250 VHLLNILRYVFGlfTVDRETIYAWFLFSH 278

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
                 ....*....|....*....|....*....|....
gi 946974170  72 YGREFKTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:cd15320  242 FKRETKVLKTLSVIMGVFVCCWLPFFILNCMVPF 275

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 946974170  16 CQFRSvmRMDYMVYVSFLTLiLIPLVVMCAIYLDIFYV-------IRNKL----------------SQNFSGSKEAGAFY 72
Cdd:cd15058  158 CDFRT--NMAYAIASSVVSF-YIPLLIMIFVYARVFLIatrqlqlIDKRRlrfqsecpapqttspeGKRSSGRRPSRLTV 234

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 946974170  73 GREFKTAKSLSLVLFLFALSWLPLSIINCIIYFDGEVPEVALYL 116
Cdd:cd15058  235 VKEHKALKTLGIIMGTFTLCWLPFFIANIINVFNRNLPPGEVFL 278

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 946974170  30 VSFLTLILIPLVVMCAIYLDIFYVIRNKL-SQNFSGSKEAGAFYGREFKTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:cd15314  167 VGSVFSFYIPAVIMLCIYLKIFLVAQRQArSIQSARTKSGASSSKMERKATKTLAIVMGVFLLCWTPFFLCNIIDPF 243

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 946974170  29 YVSFLTLIL---IPLVVMCAIYLDIFYVIRnklsqnfsgskeagafygREFKTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:cd15049  162 AITFGTAIAafyLPVLVMTILYWRIYRETA------------------RERKAARTLSAILLAFIITWTPYNILVLVSTF 223

                         90
                 ....*....|...
gi 946974170 106 -DGEVPEVALYLG 117
Cdd:cd15049  224 cAKCIPDTLWSFG 236

beta-3 adrenergic receptors (adrenoceptors), member of the class A family of seven-transmembrane G protein-coupled receptors; The beta-3 adrenergic receptor (beta-3 adrenoceptor), also known as beta-3 AR, is activated by adrenaline and plays important roles in regulating cardiac function and heart rate. 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 betrayers can lead to cardiac dysfunction such as arrhythmias or heart failure.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 946974170  16 CQFrsVMRMDYMVYVSFLTLILiPLVVMCAIYLDIFYVIRNKL-------------------SQNFSGSKEAGAFYGREF 76
Cdd:cd15959  159 CDF--VTNMPYAIVSSTVSFYV-PLLVMIFVYVRVFVVATRQVrlirkdkvrfppeesppaeSRPACGRRPSRLLAIKEH 235

                         90       100
                 ....*....|....*....|....*....
gi 946974170  77 KTAKSLSLVLFLFALSWLPLSIINCIIYF 105
Cdd:cd15959  236 KALKTLGIIMGTFTLCWLPFFVANIIKVF 264

G protein-coupled receptor 83, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR83, also known as GPR72, is widely expressed in the brain, including hypothalamic nuclei which is involved in regulating energy balance and food intake. The hypothalamic expression of GPR83 is tightly regulated in response to nutrient availability and is decreased in obese mice. A recent study suggests that GPR83 has a critical role in the regulation of systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. GPR83 shares a significant amino acid sequence identity with the tachykinin receptors, however its endogenous ligand is unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 946974170  26 YMVYVSFLTLILIPLVVMCAIYLDIFYV--IRNKLSQnfSGSKEAGAFYGREFKTAKSLSLVLFLFALSWLPLSIINCII 103
Cdd:cd15389  167 YLDLATFILQYVLPLLIIGVAYTRVAKKlwLRNAIGD--VTTEQYVAQRRKKKKTIKMLMLVVLLFAICWLPLNCYHVLL 244

                         90
                 ....*....|...
gi 946974170 104 YFDGEVPEVALYL 116
Cdd:cd15389  245 SSHPIRSNSALFF 257