transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 182 SPYVVNFLVPSGILIAIDALSFYLPLESGNCAPFKMTVLLGYSVFLLMMNDLLPATSTSShaSLVrphpsrdqkrGVYFA 261
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGT--PLI----------GVYFV 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 262 LCLSLMVGSLLETIFITHLLHvattqplplprwlhslllhctgqgrccptapqkgnkgpgltpthlpgvkepevsagqmp 341
Cdd:cd19063   69 VCLALMVLSLLETILIVKLLH----------------------------------------------------------- 89

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 223468705 342 gpgeaeltggsewtraqreheaqkqhsvelWVQFSHAMDALLFRLYLLFMASSIITVICLWN 403
Cdd:cd19063   90 ------------------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 182 SPYVVNFLVPSGILIAIDALSFYLPLESGNCAPFKMTVLLGYSVFLLMMNDLLPATSTSShaSLVrphpsrdqkrGVYFA 261
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGT--PLI----------GVYFV 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 262 LCLSLMVGSLLETIFITHLLHvattqplplprwlhslllhctgqgrccptapqkgnkgpgltpthlpgvkepevsagqmp 341
Cdd:cd19063   69 VCLALMVLSLLETILIVKLLH----------------------------------------------------------- 89

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 223468705 342 gpgeaeltggsewtraqreheaqkqhsvelWVQFSHAMDALLFRLYLLFMASSIITVICLWN 403
Cdd:cd19063   90 ------------------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit E (5HT3E); may include subunits C and D (5-HT3C,D); This subfamily contains extracellular domain of subunit E of serotonin 5-HT3 receptor (5-HT3ER), encoded by the HTR3E gene, and may also contain subunits C and D, all three encoding genes forming a cluster on chromosome 3. Data show that 5-HT3C, 5-HT3D, and 5-HT3E subunits are co-expressed with 5-HT3A in cell bodies of myenteric neurons, and that 5-HT3A and 5-HT3D are expressed in submucosal plexus of the human large intestine while HTR3E is restricted to the colon, intestine, and stomach. None of these subunits can form functional homopentamers, but, upon co-expression with the 5-HT3A subunit, they give rise to functional receptors that differ in maximal responses to 5-HT, and thus modulate 5-HT3 receptor's pharmacological profile. HTR3A and HTR3E polymorphisms have been shown to remarkably up-regulate the expression of 5-HT3 receptors, which have been proved to cause the gastric functional disorders including emesis, eating disorders and IBS-D.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705  23 DSHLQLVTSFLWLNM--------WNPDECGGIKKSGMATENLWLSDVFIEESVD--QTPAGLMASMS-----IVKATSNT 87
Cdd:cd19013   48 NEKAQLLTTFLWLRLvwdneflsWDPEECEGVTKISVPRENLWVPDIFINEFMDedKSPKVPYVYVShtgrvRDDKPVRV 127

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705  88 ISQCGWSA------SANWTPSISPSMDRgeRSPSALSPTqvTRAWRRMSRSfqihhRTSFRTRREWVLLGIQKRTIKVTV 161
Cdd:cd19013  128 VSSCNLDIftfpfdIQNCTLTFGSYLHT--VDDIKLFLL--LSVEEILKNS-----RKVLTTQGEWELVDIKAAKAKLSF 198

                        170
                 ....*....|....*..
gi 223468705 162 ATNQYEQAIFHVAIRRR 178
Cdd:cd19013  199 GEELYDEITFYVIIRRR 215

transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 182 SPYVVNFLVPSGILIAIDALSFYLPLESGNCAPFKMTVLLGYSVFLLMMNDLLPATSTSShaSLVrphpsrdqkrGVYFA 261
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGT--PLI----------GVYFV 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 262 LCLSLMVGSLLETIFITHLLHvattqplplprwlhslllhctgqgrccptapqkgnkgpgltpthlpgvkepevsagqmp 341
Cdd:cd19063   69 VCLALMVLSLLETILIVKLLH----------------------------------------------------------- 89

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 223468705 342 gpgeaeltggsewtraqreheaqkqhsvelWVQFSHAMDALLFRLYLLFMASSIITVICLWN 403
Cdd:cd19063   90 ------------------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, and ZAC; This superfamily contains the transmembrane (TM) domain of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The ligand-gated ion channels (LGICs) in this family are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 184 YVVNFLVPSGILIAIDALSFYLPLESGNCAPFKMTVLLGYSVFLLMMNDLLPATSTSShaSLVrphpsrdqkrGVYFALC 263
Cdd:cd19051    3 YVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTSDSV--PLI----------GIYLLAT 70

                         90       100
                 ....*....|....*....|
gi 223468705 264 LSLMVGSLLETIFITHLLHV 283
Cdd:cd19051   71 MVLSALSTVLTVIVLNLHHV 90

transmembrane domain of Cys-loop neurotransmitter-gated ion channels; This superfamily contains the transmembrane domain of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR), and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system where the sign of synaptic connections (excitatory or inhibitory) is determined by the charge of the ions that flow through these channels. In general, channels that conduct positive ions are excitatory, whereas channels that conduct negative ions are inhibitory. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705 184 YVVNFLVPSGILIAIDALSFYLPLESGNCAPFKMTVLLGYSVFLLMMNDLLPATSTSSHAslvrphpsrdqkrGVYFALC 263
Cdd:cd03559    2 YAVSLLLPSILIMVVSWVGFWLPPDSGERVSFKITLLLTYSVFLIIVSDTLPATPYTPLI-------------DVYFVVC 68

                         90       100       110
                 ....*....|....*....|....*....|..
gi 223468705 264 LSLMVGSLLETIFITHLLHVATTQPLPLPRWL 295
Cdd:cd03559   69 MALLFIALLETIFIVRLVHKQDRVGYVIDRLL 100

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 223468705 184 YVVNFLVPSgILIAIDA-LSFYLPLESGNcapfKMT----VLLGYSVFLLMMNDLLPATSTS 240
Cdd:cd19064    3 YTVNLIIPC-VLISFLTvLVFYLPADSGE----KITlsisVLLALTVFLLLIAEIIPPTSLV 59

extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (beta3), encoded by the CHRNB3 gene. CHRNB3 polymorphisms have been reported to potentially affect nicotine-induced upregulation of nicotinic and to be associated with disorders such as schizophrenia, autism, and cancer. Beta3 subunit is depleted in the striatum of Parkinson's disease patients. Rare variants in CHRNB3 are also implicated in risk for alcohol and cocaine dependence and independently associated with bipolar disorder. Human alpha6beta2beta3* (* indicating possible additional assembly partners) nAChRs on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease; (alpha6beta2)(alpha4beta2)beta3 nAChR is essential for addiction to nicotine and a target for drug development for smoking cessation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705  23 DSHLQLVTSFLWLNM--------WNPDECGGIKKSGMATENLWLSDVFIEESVDQTPAGLMASMSIVKatsntisqcgWS 94
Cdd:cd19026   16 DEKNQLMTTNVWLKQewmdhklrWNPEDYGGITSIRVPSESLWLPDIVLFENADGRFEGSLMTKAIVK----------YN 85

                         90
                 ....*....|
gi 223468705  95 ASANWTPSIS 104
Cdd:cd19026   86 GTVTWTPPAS 95

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 223468705  23 DSHLQLVTSFLWLNM--------WNPDECGGIKKSGMATENLWLSDVFIEESVDQTPAGlmASMSIVKATSNTISqcgWS 94
Cdd:cd19018   43 DEKNQLMTTNVWLKQewidvklrWNPDDYAGITSIRVPSDSIWIPDIVLYDNADGRFEG--TSTKTVVRYDGTIT---WT 117

                 ....*...
gi 223468705  95 ASANWTPS 102
Cdd:cd19018  118 PPANYKSS 125