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 11559956 236 LAYVVSLLIPSIFLMLVDLGSFYLPPNCRARIVFKTNVLVGYTVFRVNMSDEVPRSAGCTSLIGVFFTVCMALLVLSLSK 315
Cdd:cd19063   1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGTPLIGVYFVVCLALMVLSLLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 316 SILLIKFLYeerhseqerplmclrgdsdanesrlylrapcaedtespvrqehqvpsdtlkdfwfqlqsinnslrtrdqvy 395
Cdd:cd19063  81 TILIVKLLH----------------------------------------------------------------------- 89

                       170       180       190
                ....*....|....*....|....*....|....*..
gi 11559956 396 qkeveWLAILCHFDQLLFRIYLAVLGLYTVTLCSLWA 432
Cdd:cd19063  90 -----WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956    30 RLTRQLLQQYHKEVRPVYnWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAI 109
Cdd:TIGR00860  33 KLLDELLKNYDARVRPVF-GGPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSI 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956   110 WAPDIIINEFVDVERSP-DLPYVYVNS--SGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLgFLRN 186
Cdd:TIGR00860 112 WVPDIFFYNEKDARFHGiTMTNVLVRIhpNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKL-EWKE 190

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956   187 QEDIENDKRSFLNDSEWQLLSVTST-YHIRQSSAGDFAQIRFNVVIRRCPLAYVVSLLIPSIFLMLVDLGSFYLPPNCR- 264
Cdd:TIGR00860 191 QGAVQVDDSLFISLPEFELLGVYGTrYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADASg 270

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956   265 ARIVFKTNVLVGYTVFRVNMSDEVPRSAGcTSLIGVFFTVCMALLVLSLSKSILLI-----KFLYEERHSEQERP--LMC 337
Cdd:TIGR00860 271 ARVSLGITTLLTMTTFSSGVRESLPAVSY-VKAIDVYFAVCMAFVFLALLETAFVNyvhhkDPAQGKRHLLLERCawRLC 349

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956   338 LRGDSDANESRLYLRAPCA----------EDTESPVRQEHQV----PSDTLKDFWFQLQSINNSLRTRDQVYQKEV--EW 401
Cdd:TIGR00860 350 KQEPGEDYRRPALDHASLSsvemrakdggRGLESPTERQRLLhsppPAEGDLDLAGILEEVRIAHRFRKRDESEEVvrDW 429

                         410       420       430
                  ....*....|....*....|....*....|
gi 11559956   402 LAILCHFDQLLFRIYLAVLGLYTVTLCSLW 431
Cdd:TIGR00860 430 KFRAKVIDKLSRMAFPLAFLLFNIGYWMSY 459

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 11559956 236 LAYVVSLLIPSIFLMLVDLGSFYLPPNCRARIVFKTNVLVGYTVFRVNMSDEVPRSAGCTSLIGVFFTVCMALLVLSLSK 315
Cdd:cd19063   1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGTPLIGVYFVVCLALMVLSLLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 316 SILLIKFLYeerhseqerplmclrgdsdanesrlylrapcaedtespvrqehqvpsdtlkdfwfqlqsinnslrtrdqvy 395
Cdd:cd19063  81 TILIVKLLH----------------------------------------------------------------------- 89

                       170       180       190
                ....*....|....*....|....*....|....*..
gi 11559956 396 qkeveWLAILCHFDQLLFRIYLAVLGLYTVTLCSLWA 432
Cdd:cd19063  90 -----WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit A (5HT3A); This subfamily contains extracellular domain of subunit A of serotonin 5-HT3 receptor (5-HT3AR), encoded by the HTR3A gene. 5-HT3A subunit forms a homopentameric complex or a heterologous combination with other subunits (B-E). Heteromeric combination of A and B subunits provides the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. 5-HT3A receptors are located in the dorsal vagal complex of the brainstem and in the gastrointestinal (GI) tract, and form a channel circuit that controls gut motility, secretion, visceral perception, and the emesis reflex. These receptors are implicated in several GI and psychiatric disorder conditions including anxiety, depression, bipolar disorder, and irritable bowel syndrome (IBS). Several 5-HT3AR antagonists, such as the isoquinoline Palonosetron, are in clinical use to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. SNPs in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  28 LHRLTRQLLQQYHKEVRPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLS 107
Cdd:cd19011   1 LLRLSDHLLEGYKKGVRPVRDWRKPTTVSIDVMVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNVTQLSIPTD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 108 AIWAPDIIINEFVDVERSPDLPYVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQ 187
Cdd:cd19011  81 SIWVPDILINEFVDVGKSPEIPYVYVNHEGEVQNYKPIQVVTACSLDIYNFPFDVQNCSLTFTSWLHTIQDINISLWRSP 160

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 11559956 188 EDIENDKRSFLNDSEWQLLSVTSTYHIRQSSAGD-FAQIRFNVVIRR 233
Cdd:cd19011 161 EEVKSDKSVFMNQGEWELLGVLPQYREFSIDISDsYAEMKFYVVIRR 207

extracellular domain of serotonin 5-HT3 receptor; This family contains extracellular domain of serotonin 5-HT3 receptor which belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs). This ion 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 11559956  25 NSSLHRLTRQLLQQYHKEV----RPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQ 100
Cdd:cd18996   1 NCSYYDVLKALNKTFNSLHltytRPVKNWTPPTTVYLDLTLYAILDVDEKLQTLTTYIWLEMVWFNEFLSWNPEQFCGIS 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 101 EISLPLSAIWAPDIIINEFVDVERSPDLPYVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDID 180
Cdd:cd18996  81 KVSVPEDTLWKPDILIYEMTDKDKSPKIPYVYVSNNGTVRNYKPLQVVSTCSLDIYKFPFDTQNCNLTFSSFLHTVNDII 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....
gi 11559956 181 LGFLRNQEDI-ENDKRSFLNDSEWQLLSVTSTYHIRQSSAGDFAQIRFNVVIRR 233
Cdd:cd18996 161 LNPGSNSEEItSESKEIFQTQGEWELLNIKVSDEKLSLLGNSFDQIVYQITIKR 214

Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956    30 RLTRQLLQQYHKEVRPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAI 109
Cdd:pfam02931   3 RLLDDLLSGYDKLVRPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSDKI 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956   110 WAPDIIINEFVDVERSPDLPY--VYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQ 187
Cdd:pfam02931  83 WKPDIVLYNKADGIHEVTTPNtnVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDDDP 162

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|...
gi 11559956   188 EDIENDK---RSFLNDSEWQLLSVTSTYHIrqSSAGDFAQ----IRFNVVIRR 233
Cdd:pfam02931 163 PVVELEEidlSDFWLNGEWDIVDVPAKRRE--YPYGCYSEltgdVTFYFTLRR 213

extracellular domain (LBD) of cationic Cys-loop neurotransmitter-gated ion channels; This superfamily contains the extracellular domain (ECD) 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. 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. 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 11559956  53 TTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVDVERSPDLP--Y 130
Cdd:cd18989   1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSLDLLGDSntL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 131 VYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQEDIENdkrsFLNDSEWQLLSVTS 210
Cdd:cd18989  81 VRVSSDGTVTWVPPGVLTTSCDIDVTYFPFDTQTCSLRFGSWSYTTDEINLTPSSNGVDLED----YEENGEWELLSTSV 156

                       170       180
                ....*....|....*....|...
gi 11559956 211 TYHIRQSSAGDFAQIRFNVVIRR 233
Cdd:cd18989 157 SREEDKYCNETYSELTFTITLKR 179

extracellular domain of nicotinic acetylcholine receptor; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  53 TTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVDVERSPDLPY-V 131
Cdd:cd18997   1 VNVTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSYKTnV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 132 YVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQEDIENdkrsFLNDSEWQLLSVTST 211
Cdd:cd18997  81 IVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTVDLSD----YIENGEWDLLGAPAK 156

                       170       180
                ....*....|....*....|....
gi 11559956 212 YHIRQSSAGD--FAQIRFNVVIRR 233
Cdd:cd18997 157 RNVVKYSCCPepYPDVTFTIHIRR 180

extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (CHRNA3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (alpha3), encoded by the CHRNA3 gene, and likely plays a role in neurotransmission. The alpha3 subunit is expressed in the aorta and macrophages, and may play a regulatory role in the process of vascular inflammation. One of the most broadly expressed subtype is the alpha3beta4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability. The exact pentameric stochiometry of alpha3beta4 receptor is not known and functional assemblies with varying subunit stoichiometries are possible. Alpha4 plays a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages, via mechanisms involving the modulations of multiple cell signaling pathways. Polymorphisms in this gene (CHRNA3) have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  29 HRLTRQLLQQYHKEVRPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSA 108
Cdd:cd19016   2 HRLFERLFEDYNEIIRPVANVSDPVIIQFEVSMSQLVKVDEVNQIMETNLWLKHIWNDYKLKWNPSDYGGAEFMRVPAEK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 109 IWAPDIII-NEFVDVERSPDLPYVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQ 187
Cdd:cd19016  82 IWKPDIVLyNNAVGDFQVDDKTKALLKYTGEVTWIPPAIFKSSCKIDVTYFPFDYQNCTMKFGSWSYDKAKIDLVLIGSS 161

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|
gi 11559956 188 EDIendkRSFLNDSEWQLLSVTSTYH-IRQSSAGD-FAQIRFNVVIRRCP 235
Cdd:cd19016 162 MNL----KDYWESGEWAIIKAPGYKHdIKYNCCEEiYPDITYSLYIRRLP 207

nicotinic acetylcholine receptor (nAChR) subunit extracellular domain in molluscs and annelids; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit found in molluscs, including several Lymnaea nAChRs, and annelids that are mostly uncharacterized. To date, 12 Lymnaea nAChRs have been identified which can be subdivided in two subtypes according to the residues that may be contributing to the selectivity of ion conductance. Phylogenetic analysis of the nAChR gene sequences suggests that anionic nAChRs in molluscs probably evolved from cationic ancestors through amino acid substitutions in the ion channel pore which is a mechanism different from acetylcholine-gated channels in other invertebrates.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  53 TTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVD---VERSPDLp 129
Cdd:cd19033   1 VTVEFGLQLIQILDLDENNQVLTTNVWSRYRWTDYHLRWNPEDYGGVTHVRIPPDKIWTPDIKLYNYADerlEERREAM- 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 130 yVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQEDIenDKRSFLNDSEWQLLSVT 209
Cdd:cd19033  80 -VVVYSTGTVLWMPQAIYKSTCEIDIKYFPFDTQTCYLKFGSWTYDGTRLDITFYDNEEEI--DLTDYIESNEWEILAYP 156

                       170       180
                ....*....|....*....|....*.
gi 11559956 210 STYHIRQSSAGD--FAQIRFNVVIRR 233
Cdd:cd19033 157 AVKNVKYYPCCPepYPDLTFFLVIKR 182

extracellular domain of neuronal acetylcholine receptor subunit alpha 9 (CHRNA9); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 9 (alpha9), encoded by the CHRNA9 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Mammalian alpha9 subunits can form functional homomeric alpha9 receptors as well as the heteromeric alpha9alpha10 receptors, the latter being atypical since the heteromeric alpha9alpha10 receptor is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms. CHRNA9 polymorphisms are associated with non-small cell lung cancer, and effect of a particular SNP (rs73229797) and passive smoking exposure on risk of breast malignancy has been observed.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  29 HRLTRQLLQQYHKEVRPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSA 108
Cdd:cd19022   2 QKLFNDLFEDYSNALRPVEDTDKVLNVTLQITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDGLDSIRIPSNL 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 109 IWAPDIIINEFVDVERS-PDLPYVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQ 187
Cdd:cd19022  82 VWRPDIVLYNKADDEFSePVNTNVVLRYDGKITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNGNQVDIINALDS 161

                       170
                ....*....|....*...
gi 11559956 188 EDIENdkrsFLNDSEWQL 205
Cdd:cd19022 162 GDLSD----FVEDVEWEV 175

extracellular domain of nicotinic acetylcholine receptor subunit beta-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor alpha-subunits (L-AChR), UNC-38, UNC-63, and LEV-8, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1 found in this subfamily. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChR subunits have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Dbeta1 subunits in dopaminergic neurons play a role in acute locomotor hyperactivity caused by nicotine in male Drosophila. Mutations of Dbeta2 or Dalpha1 nAChR subunits in Drosophila strains have significantly lower neonicotinoid-stimulated release, but no changes in nicotine-stimulated release; they are highly resistant to the neonicotinoids nitenpyram and imidacloprid. This family also includes a novel nAChR found in Aplysia bag cell neurons (neuroendocrine cells that control reproduction) which is a cholinergic ionotropic receptor that is both, nicotine insensitive and acetylcholine sensitive.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  30 RLTRQLLQQYHKEVRPVYNWAEATTVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAI 109
Cdd:cd19032   4 RLVRDLFRGYNYLIRPVRNMSEPVEVNFGLALIQLINVDEKNQIMKTNVWLTMYWNDYQLKWDPADYGGIKVIRVPPDKV 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 110 WAPDIIINEFVDVERSPDL-PYVYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQE 188
Cdd:cd19032  84 WKPDIVLFNNADGNYEVSYkSNVLIYSTGEVLWVPPAIYKSSCTIDVEYFPFDQQECEMKFGSWTFNGDEVSLDLYNNKK 163

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*.
gi 11559956 189 DIE-NDkrsFLNDSEWQLLSVTSTYHIRQSSAGDFAQIRFNVVIRR 233
Cdd:cd19032 164 FVDlSD---YWKSGTWDIIDVPGQLVNKDDAGPTETDIIFKIKIRR 206

extracellular domain of neuronal acetylcholine receptor subunit alpha 7 (CHRNA7); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 7 (alpha7), encoded by the CHRNA7 gene. Alpha7 subunits form a homo-pentameric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. This protein is ubiquitously expressed in both the central nervous system and in the periphery, in several tissues, including adrenal, small intestine, testis, and stomach. CHRNA7 is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. It is also genetically linked to other disorders with cognitive deficits, including bipolar disorder, ADHD, Alzheimer's disease, and Rett syndrome. An evolutionarily recent partial duplication of CHRNA7 on chromosome 15 forms a new gene, CHRFAM7A or FAM7A, which encodes the protein dup-alpha7. This protein assembles with alpha7 subunits, results in fewer binding sites and is a dominant negative regulator of alpha7 nAChR function.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  54 TVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVDvERSpDLPY--- 130
Cdd:cd19020   3 TVYFSLSLMQIMDVDEKNQVLTTNIWLQMYWTDHYLQWNASEYPGVKNVRFPDGQIWKPDILLYNSAD-ERF-DATFhtn 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 131 VYVNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLgflrnqEDIENDKRSFLNDSEWQLLSVTS 210
Cdd:cd19020  81 VLVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQKCNLKFGSWTYGGWSLDL------QMQEADISGYISNGEWDLVGVPG 154

                       170       180
                ....*....|....*....|....*
gi 11559956 211 --TYHIRQSSAGDFAQIRFNVVIRR 233
Cdd:cd19020 155 krNEKFYECCKEPYPDVTFTVTMRR 179

extracellular domain of nicotinic acetylcholine receptor subunit alpha 6 (CHRNA6); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 6 (alpha6), encoded by the CHRNA6 gene. Human (alpha6beta2)(alpha4beta2)3 nicotinic acetylcholine receptors (AChRs) are essential for addiction to nicotine and a target for drug development for smoking cessation. In xenopus oocytes, data show efficient expression of (alpha6beta2)2beta3 AChR subunits with only small changes in alpha6 subunits, while not altering AChR pharmacology or channel structure. Alternatively spliced transcript variants have been observed for this gene. Single nucleotide polymorphisms in this gene have been associated with both nicotine and alcohol dependence. CHRNA6 has a cellular expression signature for retinal ganglion cells with high correlation to Thy1, a known marker, and is preferentially expressed by retinal ganglion cells (RGCs) in the young and adult mouse retina and expression is reduced in glaucoma. A genetic variant in CHRNB3#CHRNA6 cluster is associated with esophageal adenocarcinoma.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  54 TVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIII-NEFVDVERSPDLPYVY 132
Cdd:cd19019   2 TVHFEVAITQLVNVDEVNQIMETNLWLRHIWNDYKLRWDPREYDGIEFMRVPADKIWKPDIVLyNNAVGDFQVEGKTKAL 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 133 VNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQEDIENdkrsFLNDSEWQLLSVTSTY 212
Cdd:cd19019  82 LKYNGMITWTPPAIFKSSCPMDITFFPFDHQNCSLKFGSWTYDKAKIDLLIIGSKVDMND----FWENSEWEIVDASGYK 157

                       170       180
                ....*....|....*....|...
gi 11559956 213 H-IRQSSAGD-FAQIRFNVVIRR 233
Cdd:cd19019 158 HdIKYNCCEEiYTDITYSFYIRR 180

extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) 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. 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. The ECD contains the ligand binding sites for these receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  54 TVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIII-NEFVDVERSPDLPYVY 132
Cdd:cd03558   2 TVTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFyNNKDADFVTTDNVLIR 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 133 VNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDlgFLRNQEDIENDKRSFLndSEWQLLSVTSTY 212
Cdd:cd03558  82 LSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIE--LVWDSERPDQADFLEL--PEWDIVEKRGRY 157

                       170       180
                ....*....|....*....|.
gi 11559956 213 HIRQSSAGDFAQIRFNVVIRR 233
Cdd:cd03558 158 CTVVYNTGIYSDITYRFRLKR 178

extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  54 TVYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVDVERSPDL-PYVY 132
Cdd:cd19027   2 SIKLQLSLAQLISVNEREQIMTTNVWLNQEWTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNADGTYEVSVyTNAI 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956 133 VNSSGTIRNHKPIQVVSACSLQTYAFPFDIQNCSLTFNSILHTVEDIDLGFLRNQEDIENdkrsFLNDSEWQLLSVTSTY 212
Cdd:cd19027  82 VQNNGSVAWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDHTEIDMVLKTPTASMDD----FTPSGEWDIVALPGRR 157

                       170       180
                ....*....|....*....|.
gi 11559956 213 HIRQSSAgDFAQIRFNVVIRR 233
Cdd:cd19027 158 TVNPLDP-TYVDVTYDFIIKR 177

extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11559956  55 VYLDLCVHAVLDVDVQNQKLKTSMWYREVWNDEFLSWNSSLFDDIQEISLPLSAIWAPDIIINEFVDVERSPDL-PYVYV 133
Cdd:cd19021   3 VELQLSLLQIIDVDEKNQVLITNAWLQMYWVDIYLSWDQYEYPGVQNLRFPSDQIWVPDILLYNSADERFDATFhTNVLV 82