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 375298707  46 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 110
Cdd:cd19013    1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 111 TKMSMAAKNLWLPDIFIIELcvsragqrevpspgshrdhslplgplMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNL 190
Cdd:cd19013   80 TKISVPRENLWVPDIFINEF--------------------------MDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNL 133

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 191 DIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIR 270
Cdd:cd19013  134 DIFTFPFDIQNCTLTFGSYLHTVDDIKLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIR 213

                 ..
gi 375298707 271 RR 272
Cdd:cd19013  214 RR 215

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 375298707  46 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 110
Cdd:cd19013    1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 111 TKMSMAAKNLWLPDIFIIELcvsragqrevpspgshrdhslplgplMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNL 190
Cdd:cd19013   80 TKISVPRENLWVPDIFINEF--------------------------MDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNL 133

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 191 DIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIR 270
Cdd:cd19013  134 DIFTFPFDIQNCTLTFGSYLHTVDDIKLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIR 213

                 ..
gi 375298707 271 RR 272
Cdd:cd19013  214 RR 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 375298707 274 SLYVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLE 351
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATaiGTPLIGVYFVVCLALMVLSLLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 352 TIFITHLLHvattqppplprwlhslllhcnspgrccptapqkenkgpgltpthlpgvkepevsagqmpgpaeaeltggse 431
Cdd:cd19063   81 TILIVKLLH----------------------------------------------------------------------- 89

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|
gi 375298707 432 wtraqreheaqkqhsvelWLQFSHAMDAMLFRLYLLFMASSIITVICLWN 481
Cdd:cd19063   90 ------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

Neurotransmitter-gated ion-channel transmembrane region; This family includes the four transmembrane helices that form the ion channel.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  280 LLVPSGFLVAIDALSFYLPVKS-GNRVPFKITLLLGYNVFLLMMSDLLP-TS-GTPLIGVYFALCLSLMVGSLLETIFIt 356
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAvGEKVTLGITVLLTMTVFLLLIRESLPkTSyVVPLIGKYLLFCMVFVFLSLVETVFV- 79

                          90       100
                  ....*....|....*....|...
gi 375298707  357 HLLHVATTQPPPLPRWLHSLLLH 379
Cdd:pfam02932  80 LNVHHRSPSTHKMPPWVRKIFLE 102

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 375298707  46 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 110
Cdd:cd19013    1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 111 TKMSMAAKNLWLPDIFIIELcvsragqrevpspgshrdhslplgplMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNL 190
Cdd:cd19013   80 TKISVPRENLWVPDIFINEF--------------------------MDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNL 133

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 191 DIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIR 270
Cdd:cd19013  134 DIFTFPFDIQNCTLTFGSYLHTVDDIKLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIR 213

                 ..
gi 375298707 271 RR 272
Cdd:cd19013  214 RR 215

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 375298707   70 RPVTNiSVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIElcvsr 134
Cdd:TIGR00860  47 RPVFG-GPPVTVSFNLFLRSIMDVdeknmdyttniwlrqEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYN----- 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  135 agqrevpSPGSHRDHSLPlgplmdvdktPKGLTAYVSNeGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVD 214
Cdd:TIGR00860 121 -------EKDARFHGITM----------TNVLVRIHPN-GSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTN 182

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  215 --SMLLDMEKEVweitDASRNILQTHGEWELLGLSK---ATAKLSRGGnlYDQIVFYVAIRRRPSLYVINLLVPSGFLVA 289
Cdd:TIGR00860 183 diKLEWKEQGAV----QVDDSLFISLPEFELLGVYGtryCTSETNTGE--YPCLTFSFVLRRRPLYYLLQLYIPSILIVI 256

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  290 IDALSFYLPV-KSGNRVPFKITLLLGYNVFLLMMSDLLP-TSGTPLIGVYFALCLSLMVGSLLETIFITHLLHvatTQPP 367
Cdd:TIGR00860 257 LSWVSFWLPAdASGARVSLGITTLLTMTTFSSGVRESLPaVSYVKAIDVYFAVCMAFVFLALLETAFVNYVHH---KDPA 333

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  368 PLPRwlHSLLLHCnsPGRCCPTAPQKENKGPGLTPTHLPGVKEPEVSAGQ-------------MPGPAEAELTGGSEWTR 434
Cdd:TIGR00860 334 QGKR--HLLLERC--AWRLCKQEPGEDYRRPALDHASLSSVEMRAKDGGRglespterqrllhSPPPAEGDLDLAGILEE 409

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|
gi 375298707  435 AQREHEAQKQHSVE----LWLQFSHAMDAMLFRLYLLFmasSIITVICLW 480
Cdd:TIGR00860 410 VRIAHRFRKRDESEevvrDWKFRAKVIDKLSRMAFPLA---FLLFNIGYW 456

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 375298707  66 RKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIEL 130
Cdd:cd19011   13 KKGVRPVRDWRKPTTVSIDVMVYAILNVdeknqvlttyiwyrqYWTDEFLQWNPEDFDNVTQLSIPTDSIWVPDILINEF 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 131 cvsragqrevpspgshrdhslplgplMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFL 210
Cdd:cd19011   93 --------------------------VDVGKSPEIPYVYVNHEGEVQNYKPIQVVTACSLDIYNFPFDVQNCSLTFTSWL 146

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375298707 211 YTVDsmllDMEKEVWEITDA---SRNILQTHGEWELLG-LSKATAKLSRGGNLYDQIVFYVAIRRR 272
Cdd:cd19011  147 HTIQ----DINISLWRSPEEvksDKSVFMNQGEWELLGvLPQYREFSIDISDSYAEMKFYVVIRRR 208

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 375298707   70 RPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIElcvSR 134
Cdd:pfam02931  17 RPVANGSDPVTVSIGLYLQQIIDVdeknqdlttnvwlrqTWTDPRLAWNPEDYGGITSLRLPSDKIWKPDIVLYN---KA 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  135 AGQREVPSPGSHrdhslplgplmdvdktpkgltAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVD 214
Cdd:pfam02931  94 DGIHEVTTPNTN---------------------VRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGE 152

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 375298707  215 SMLLDMEKE----VWEITDASRNILQthGEWELLGLSKATAKLSRGG--NLYDQIVFYVAIRRRP 273
Cdd:pfam02931 153 EVDLRWDDDppvvELEEIDLSDFWLN--GEWDIVDVPAKRREYPYGCysELTGDVTFYFTLRRKP 215

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 375298707  81 VNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIElcvSRAGQrevpspgs 145
Cdd:cd18997    3 VTFGLTLRQIIDVdeknqvlttnvwlrqEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYN---NADGD-------- 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 146 hrdhslpLGPLMDVDktpkgltAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVW 225
Cdd:cd18997   72 -------FDSSYKTN-------VIVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTV 137

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 375298707 226 EITDASRNilqthGEWELLGlskATAKLSR-----GGNLYDQIVFYVAIRRR 272
Cdd:cd18997  138 DLSDYIEN-----GEWDLLG---APAKRNVvkyscCPEPYPDVTFTIHIRRK 181

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 375298707 276 YVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLETI 353
Cdd:cd19051    3 YVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTsdSVPLIGIYLLATMVLSALSTVLTV 82

                 ....*...
gi 375298707 354 FITHLLHV 361
Cdd:cd19051   83 IVLNLHHV 90

extracellular domain of nicotinic acetylcholine receptor subunit beta 2 (CHRNB2); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 2 (beta2), encoded by the CHRNB2 gene. The most abundant nicotinic subtype in the human brain is alpha4beta2 receptor which is known to assemble in two functional subunit stoichiometries, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, the latter having a much higher affinity for both acetylcholine and nicotine. This subtype is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism, and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Thus, pharmacological ligands targeting this subtype have been researched and developed as a treatment approach implicated in these diseases. They include agonists such as varenicline and cytisine used as smoking cessation aids, as well as positive allosteric modulators (PAMs) such as desformylflustrabromine (dFBr), which are ligands that bind to nicotinic receptors at sites other than the orthosteric site where acetylcholine binds, and are not able to act as agonists on nAChR.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  60 LNSVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPD 124
Cdd:cd19025    7 LGPSRYNKLIRPATNGSQLVTVQLMVSLAQLISVhereqimttnvwltqEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPD 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 125 IFIIElcvSRAGQREVPSPGShrdhslplgplmdvdktpkgltAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTL 204
Cdd:cd19025   87 VVLYN---NADGMYEVSFYSN----------------------AVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTL 141

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 375298707 205 TFSSFLYTVDSMLLDMEKEVweitdASRNILQTHGEWELLGLSKATAKlSRGGNLYDQIVFYVAIRRRP 273
Cdd:cd19025  142 KFRSWTYDRTEIDLVLRSDV-----ASLDDFTPSGEWDIVALPGRRNE-NPNDSTYVDITYDFIIRRKP 204

extracellular domain of nicotinic acetylcholine receptor subunit alpha 2 (CHRNA2); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 2 (alpha2), encoded by the CHRNA2 gene. It is specifically expressed in medial subpallium-derived amygdalar nuclei from early developmental stages to adult. This subunit is incorporated in heteropentameric neuronal nAChRs mainly with beta2 or beta4 subunits and, along with the alpha4 and alpha7, is one of the main nAChR subunits expressed in primate brain. In Xenopus laevis oocytes, when alpha2 is co-expressed with the beta2 subunit, two subtypes of alpha2beta2 nAChR are formed with either low or high ACh sensitivity. Mouse mutation studies show that alpha2 subunits in the nAChRs influence hippocampus-dependent learning and memory as well as CA1 synaptic plasticity in adolescent mice.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  70 RPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIElcvSR 134
Cdd:cd19015   17 RPVPNTSDVVIVKFGLSIAQLIDVdeknqmmttnvwlkqEWSDYKLRWNPTDFDNVTSIRVPSEMIWIPDIVLYN---NA 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 135 AGQREVpspgSHRDhslplgplmdvdktpkglTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYtvD 214
Cdd:cd19015   94 DGEFAV----THMT------------------KAHLFSTGKVKWVPPAIYKSSCSIDVTFFPFDQQNCKMKFGSWTY--D 149

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 375298707 215 SMLLDME--------KEVWEitdasrnilqtHGEWELLGL--SKATAKLSRGGNLYDQIVFYVAIRRRP 273
Cdd:cd19015  150 KAKIDLEqmeqtvdlKDYWE-----------SGEWAIVNAtgTYNSKKYDCCTEIYPDITYYFVIRRLP 207

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 375298707  95 WDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIElcvSRAGQREvpspgshrdhslplGPLMDvdktpkglTAYVSNEG 174
Cdd:cd19026   32 WMDHKLRWNPEDYGGITSIRVPSESLWLPDIVLFE---NADGRFE--------------GSLMT--------KAIVKYNG 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 175 RIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLY---TVDSMLLDMEKEVWEITDasrnilqtHGEWELLGLSKATA 251
Cdd:cd19026   87 TVTWTPPASYKSSCTMDVTFFPFDRQNCSMKFGSWTYdgnMVDLILIDENVDRKDFFD--------NGEWEILNAKGMKG 158

                        170       180
                 ....*....|....*....|
gi 375298707 252 KLSRGGNLYDQIVFYVAIRR 271
Cdd:cd19026  159 NRKDGLYSYPFITYSFVLRR 178

extracellular domain of nicotinic acetylcholine receptor subunit alpha-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha-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 (L-AChR) alpha-subunits, UNC-38, UNC-63, and LEV-8, included in this subfamily, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. Also included is the nicotinic alpha subunit MARA1 (Manduca ACh Receptor Alpha 1) which is expressed in Ca2+ responding neurons and contributes to the nicotinic responses in the neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChRs have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Alpha5 subunit is involved in alpha-bungarotoxin sensitivity while the alpha6 subunit is essential for the insecticidal effect of spinosad. nAChR agonists acetylcholine, nicotine, and neonicotinoids stimulate dopamine release in Drosophila larval ventral nerve cord and mutations in nAChR subunits affect how insecticides stimulate dopamine release.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  65 NRKPfrPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFiie 129
Cdd:cd19031   16 NRRP--RVTNDSDTLTVKLGLKLSQLIDVdeknqimttnvwleqEWYDYKLVWDPAEYGGVEMLYVPSEDIWLPDIV--- 90

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 130 LCVSRAGQREVPSpgshrdhslplgplmdvdktpkGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSF 209
Cdd:cd19031   91 LYNNADGNYEVTL----------------------MTKATLHYNGTVRWEPPAIYKSSCEIDVEYFPFDEQTCFMKFGSW 148

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 210 LYtvDSMLLDMeKEVWEITDASRNILQtHG----------EWELLglsKATAKlsRGGNLYD-------QIVFYVAIRRR 272
Cdd:cd19031  149 TY--DGFEVDL-RHVDQKYGSEDEVID-VGidlsefypsvEWDLL---EVPAR--RNEKYYPccdepypDITFNITLRRK 219

                 .
gi 375298707 273 P 273
Cdd:cd19031  220 T 220

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 375298707  81 VNISFAMS--AILDV----------VWD-----NPFISWNPEECEGITKMSMAAKNLWLPDIFIIELCVSRagQREvpsp 143
Cdd:cd19033    1 VTVEFGLQliQILDLdennqvlttnVWSryrwtDYHLRWNPEDYGGVTHVRIPPDKIWTPDIKLYNYADER--LEE---- 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 144 gsHRDhslplgPLMDVDKTpkgltayvsneGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYT---VDSMLLDM 220
Cdd:cd19033   75 --RRE------AMVVVYST-----------GTVLWMPQAIYKSTCEIDIKYFPFDTQTCYLKFGSWTYDgtrLDITFYDN 135

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....
gi 375298707 221 EKEvWEITDasrniLQTHGEWELLGLS--KATAKLSRGGNLYDQIVFYVAIRRR 272
Cdd:cd19033  136 EEE-IDLTD-----YIESNEWEILAYPavKNVKYYPCCPEPYPDLTFFLVIKRR 183

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 375298707  80 QVNISFAMSAILDVVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIielcVSRAGQREVpspgshrdhslplgplmDV 159
Cdd:cd03558   17 EVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVF----YNNKDADFV-----------------TT 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 160 DKTpkglTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLdmekeVWEITDASRNILQTHG 239
Cdd:cd03558   76 DNV----LIRLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIEL-----VWDSERPDQADFLELP 146

                 ....
gi 375298707 240 EWEL 243
Cdd:cd03558  147 EWDI 150

extracellular domain of nicotinic acetylcholine receptor subunit delta (CHRND); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit delta (delta), encoded by the CHRND gene and found in the muscle. Delta nAChR subunit forms a heteropentamer with either (alpha1)2, beta and gamma subunits in embryonic type or (alpha1)2, beta and epsilon subunits in adult type receptors. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). The slow-channel congenital myasthenic syndromes (SCCMS) are caused by prolonged opening episodes of AChR due to dominant gain-of-function mutations in the transmembrane regions of the heteropentamer. These mutations produce an increase in the channel opening rate, a decrease in the channel closing rate, or an increase in the affinity of ACh for the AChR, resulting in the stabilization of the open state or the destabilization of the closed state of the AChR.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707  60 LNSVFN----RKPFRPVTNISVPTQVNISFAMSAIL---------------DVVWDNPFISWNPEECEGITKMSMAAKNL 120
Cdd:cd19028    4 INHLFIergyNKELRPVAHKDEVVNVALALTLSNLIslkevdetlttnvwvEHGWYDHRLTWNASEYGNISILRLPPEMV 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 121 WLPDIFiieLCVSRAGQREVpspgshrdhslplgplmdvdktpkgltAY-----VSNEGRIRYKKPMKVDSICNLDIFYF 195
Cdd:cd19028   84 WLPEIV---LENNNDGQFEV---------------------------AYycnvlVYSDGFVYWLPPAIFRSSCPINVNYF 133

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 196 PFDQQNCTLTFSSFLYTVDSMLLDMEKEV---------WEITDASRniLQTHGEWELL---GLSKATAKLSRGGNLYDQI 263
Cdd:cd19028  134 PFDWQNCSLKFSSLNYNAKEINLDLKTDTddgktypveWIIIDPEG--FTENGEWEIVhkpAKKNIDPSKPPESTKYQDI 211

                        250
                 ....*....|
gi 375298707 264 VFYVAIRRRP 273
Cdd:cd19028  212 TFYLIIKRKP 221

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 375298707  69 FRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIielcVS 133
Cdd:cd19022   16 LRPVEDTDKVLNVTLQITLSQIKDMdernqiltaylwirqSWYDAYLKWDRDEYDGLDSIRIPSNLVWRPDIVL----YN 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298707 134 RAGqrevpspgshrdhslplgplmDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTV 213
Cdd:cd19022   92 KAD---------------------DEFSEPVNTNVVLRYDGKITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNG 150

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 375298707 214 DSMLLDMEKEVWEITDASRNIlqthgEWELLGLSKATAKLSRG--GNLYDQIVFYVAIRRR 272
Cdd:cd19022  151 NQVDIINALDSGDLSDFVEDV-----EWEVHGMPAVKNVITYGccSEPYPDVTFTLILKRR 206