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 38146010  31 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 95
Cdd:cd19013   1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010  96 TKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSM 175
Cdd:cd19013  80 TKISVPRENLWVPDIFINEFMDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNLDIFTFPFDIQNCTLTFGSYLHTVDDI 159

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 38146010 176 LLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRRR 231
Cdd:cd19013 160 KLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIRRR 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 38146010  31 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 95
Cdd:cd19013   1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010  96 TKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSM 175
Cdd:cd19013  80 TKISVPRENLWVPDIFINEFMDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNLDIFTFPFDIQNCTLTFGSYLHTVDDI 159

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 38146010 176 LLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRRR 231
Cdd:cd19013 160 KLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIRRR 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 38146010 233 SLYVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLE 310
Cdd:cd19063   1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATaiGTPLIGVYFVVCLALMVLSLLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 311 TIFITHLLHvattqppplprwlhslllhcnspgrccptapqkenkgpgltpthlpgvkepevsagqmpgpaeaeltggse 390
Cdd:cd19063  81 TILIVKLLH----------------------------------------------------------------------- 89

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|
gi 38146010 391 wtraqreheaqkqhsvelWLQFSHAMDAMLFRLYLLFMASSIITVICLWN 440
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 38146010   239 LLVPSGFLVAIDALSFYLPVKS-GNRVPFKITLLLGYNVFLLMMSDLLP-TS-GTPLIGVYFALCLSLMVGSLLETIFIt 315
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAvGEKVTLGITVLLTMTVFLLLIRESLPkTSyVVPLIGKYLLFCMVFVFLSLVETVFV- 79

                          90       100
                  ....*....|....*....|...
gi 38146010   316 HLLHVATTQPPPLPRWLHSLLLH 338
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 38146010  31 NCSGFGQHGADPTALNsVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGI 95
Cdd:cd19013   1 NCSGPTTPSLLSALEV-EFDRKAFRPVMNLSTPTNVNISFTLYAILGVnekaqllttflwlrlVWDNEFLSWDPEECEGV 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010  96 TKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSM 175
Cdd:cd19013  80 TKISVPRENLWVPDIFINEFMDEDKSPKVPYVYVSHTGRVRDDKPVRVVSSCNLDIFTFPFDIQNCTLTFGSYLHTVDDI 159

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 38146010 176 LLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRRR 231
Cdd:cd19013 160 KLFLLLSVEEILKNSRKVLTTQGEWELVDIKAAKAKLSFGEELYDEITFYVIIRRR 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 38146010    55 RPVTNiSVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV- 118
Cdd:TIGR00860  47 RPVFG-GPPVTVSFNLFLRSIMDVdeknmdyttniwlrqEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDAr 125

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010   119 --DKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVD--SMLLDMEKEVweitDASRNIL 194
Cdd:TIGR00860 126 fhGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNdiKLEWKEQGAV----QVDDSLF 201

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010   195 QTHGEWELLGLSK---ATAKLSRGGnlYDQIVFYVAIRRRPSLYVINLLVPSGFLVAIDALSFYLPV-KSGNRVPFKITL 270
Cdd:TIGR00860 202 ISLPEFELLGVYGtryCTSETNTGE--YPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPAdASGARVSLGITT 279

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010   271 LLGYNVFLLMMSDLLP-TSGTPLIGVYFALCLSLMVGSLLETIFITHLLHvatTQPPPLPRwlHSLLLHCnsPGRCCPTA 349
Cdd:TIGR00860 280 LLTMTTFSSGVRESLPaVSYVKAIDVYFAVCMAFVFLALLETAFVNYVHH---KDPAQGKR--HLLLERC--AWRLCKQE 352

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010   350 PQKENKGPGLTPTHLPGVKEPEVSAGQ-------------MPGPAEAELTGGSEWTRAQREHEAQKQHSVE----LWLQF 412
Cdd:TIGR00860 353 PGEDYRRPALDHASLSSVEMRAKDGGRglespterqrllhSPPPAEGDLDLAGILEEVRIAHRFRKRDESEevvrDWKFR 432

                         410       420
                  ....*....|....*....|....*..
gi 38146010   413 SHAMDAMLFRLYLLFmasSIITVICLW 439
Cdd:TIGR00860 433 AKVIDKLSRMAFPLA---FLLFNIGYW 456

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 38146010 233 SLYVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLE 310
Cdd:cd19063   1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATaiGTPLIGVYFVVCLALMVLSLLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 311 TIFITHLLHvattqppplprwlhslllhcnspgrccptapqkenkgpgltpthlpgvkepevsagqmpgpaeaeltggse 390
Cdd:cd19063  81 TILIVKLLH----------------------------------------------------------------------- 89

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|
gi 38146010 391 wtraqreheaqkqhsvelWLQFSHAMDAMLFRLYLLFMASSIITVICLWN 440
Cdd:cd19063  90 ------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

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 38146010  64 TQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFI---IELMDVDKTPKGL 125
Cdd:cd18989   1 VNVNVSFSLYSILDLdeveqtltlsgwltlTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLynsVDSLDLLGDSNTL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 126 tAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNilqthGEWELLGL 205
Cdd:cd18989  81 -VRVSSDGTVTWVPPGVLTTSCDIDVTYFPFDTQTCSLRFGSWSYTTDEINLTPSSNGVDLEDYEEN-----GEWELLST 154

                       170       180
                ....*....|....*....|....*.
gi 38146010 206 SKATAKLSRGGNLYDQIVFYVAIRRR 231
Cdd:cd18989 155 SVSREEDKYCNETYSELTFTITLKRR 180

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 38146010  73 SAILDVVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFII-----ELMDVDKTPkgltAYVSNEGRIRYKKPMKVDSIC 147
Cdd:cd18997  25 NVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYnnadgDFDSSYKTN----VIVYSDGTVTWLPPAIFKSSC 100

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 148 NLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDasrniLQTHGEWELLGlskATAKLSR-----GGNLYDQI 222
Cdd:cd18997 101 KIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTVDLSD-----YIENGEWDLLG---APAKRNVvkyscCPEPYPDV 172

                ....*....
gi 38146010 223 VFYVAIRRR 231
Cdd:cd18997 173 TFTIHIRRK 181

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 38146010  45 LNSVFNRKPFRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPD 109
Cdd:cd19025   7 LGPSRYNKLIRPATNGSQLVTVQLMVSLAQLISVhereqimttnvwltqEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPD 86

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 110 IFIIELMD-VDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVweitd 188
Cdd:cd19025  87 VVLYNNADgMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLRSDV----- 161

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....
gi 38146010 189 ASRNILQTHGEWELLGLSKATAKlSRGGNLYDQIVFYVAIRRRP 232
Cdd:cd19025 162 ASLDDFTPSGEWDIVALPGRRNE-NPNDSTYVDITYDFIIRRKP 204

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 38146010  80 WDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQ 158
Cdd:cd19027  32 WTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNADGTYEVSVYTnAIVQNNGSVAWLPPAIYKSACKIEVKHFPFDQ 111

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 38146010 159 QNCTLTFSSFLYtvDSMLLDMekeVWEITDASRNILQTHGEWELLGL 205
Cdd:cd19027 112 QNCTLKFRSWTY--DHTEIDM---VLKTPTASMDDFTPSGEWDIVAL 153

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 38146010  50 NRKPfrPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIE 114
Cdd:cd19031  16 NRRP--RVTNDSDTLTVKLGLKLSQLIDVdeknqimttnvwleqEWYDYKLVWDPAEYGGVEMLYVPSEDIWLPDIVLYN 93

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 115 LMDVDKTPKGLT-AYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYtvDSMLLDMeKEVWEITDASRNI 193
Cdd:cd19031  94 NADGNYEVTLMTkATLHYNGTVRWEPPAIYKSSCEIDVEYFPFDEQTCFMKFGSWTY--DGFEVDL-RHVDQKYGSEDEV 170

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 38146010 194 LQtHG----------EWELLglsKATAKlsRGGNLYD-------QIVFYVAIRRRP 232
Cdd:cd19031 171 ID-VGidlsefypsvEWDLL---EVPAR--RNEKYYPccdepypDITFNITLRRKT 220

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 38146010 235 YVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLETI 312
Cdd:cd19051   3 YVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTsdSVPLIGIYLLATMVLSALSTVLTV 82

                ....*...
gi 38146010 313 FITHLLHV 320
Cdd:cd19051  83 IVLNLHHV 90

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 38146010  80 WDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQ 158
Cdd:cd19026  32 WMDHKLRWNPEDYGGITSIRVPSESLWLPDIVLFENADGRFEGSLMTkAIVKYNGTVTWTPPASYKSSCTMDVTFFPFDR 111

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 38146010 159 QNCTLTFSSFLY---TVDSMLLDMEKEVWEITDasrnilqtHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRR 230
Cdd:cd19026 112 QNCSMKFGSWTYdgnMVDLILIDENVDRKDFFD--------NGEWEILNAKGMKGNRKDGLYSYPFITYSFVLRR 178

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 38146010  54 FRPVTNISVPTQVNISFAMSAILDV---------------VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV 118
Cdd:cd19022  16 LRPVEDTDKVLNVTLQITLSQIKDMdernqiltaylwirqSWYDAYLKWDRDEYDGLDSIRIPSNLVWRPDIVLYNKADD 95

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 119 DKT-PKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNIlqth 197
Cdd:cd19022  96 EFSePVNTNVVLRYDGKITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNGNQVDIINALDSGDLSDFVEDV---- 171

                       170       180       190
                ....*....|....*....|....*....|....*.
gi 38146010 198 gEWELLGLSKATAKLSRG--GNLYDQIVFYVAIRRR 231
Cdd:cd19022 172 -EWEVHGMPAVKNVITYGccSEPYPDVTFTLILKRR 206

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 38146010  57 VTNISVPTQVNISFAMSAILDVVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYVSNEGRI 135
Cdd:cd19019   9 ITQLVNVDEVNQIMETNLWLRHIWNDYKLRWDPREYDGIEFMRVPADKIWKPDIVLYNNAVGDFQVEGKTkALLKYNGMI 88

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 136 RYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLY---TVDSMLL----DMeKEVWEitdasrnilqtHGEWELLGLS-- 206
Cdd:cd19019  89 TWTPPAIFKSSCPMDITFFPFDHQNCSLKFGSWTYdkaKIDLLIIgskvDM-NDFWE-----------NSEWEIVDASgy 156

                       170       180
                ....*....|....*....|....
gi 38146010 207 KATAKLSRGGNLYDQIVFYVAIRR 230
Cdd:cd19019 157 KHDIKYNCCEEIYTDITYSFYIRR 180

extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 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. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010  79 VWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYV-SNEGRIRYKKPMKVDSICNLDIFYFPFD 157
Cdd:cd19023  31 VWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSMETNVViRSDGQIMWDSPAITKSSCKVDVSFFPFD 110

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 38146010 158 QQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNIlqthgEWELLGLSKATAKLSRG--GNLYDQIVFYVAIRRR 231
Cdd:cd19023 111 GQQCRLTFGSWTYNGNQIDILNLLDTGDLTDFVENV-----EWEVLGMPAKRNVITYGccSEPYPDVTYTLLLKRR 181

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 38146010  45 LNSVFN----RKPFRPVTNISVPTQVNISFAMSAIL---------------DVVWDNPFISWNPEECEGITKMSMAAKNL 105
Cdd:cd19028   4 INHLFIergyNKELRPVAHKDEVVNVALALTLSNLIslkevdetlttnvwvEHGWYDHRLTWNASEYGNISILRLPPEMV 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 106 WLPDIfiieLMDVDKTPKGLTAY-----VSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDME 180
Cdd:cd19028  84 WLPEI----VLENNNDGQFEVAYycnvlVYSDGFVYWLPPAIFRSSCPINVNYFPFDWQNCSLKFSSLNYNAKEINLDLK 159

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 38146010 181 KEV---------WEITDASRniLQTHGEWELL---GLSKATAKLSRGGNLYDQIVFYVAIRRRP 232
Cdd:cd19028 160 TDTddgktypveWIIIDPEG--FTENGEWEIVhkpAKKNIDPSKPPESTKYQDITFYLIIKRKP 221

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 38146010  76 LDVVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMD--VDKTPKgLTAYVSNEGRIRYKKPMKVDSICNLDIFY 153
Cdd:cd19020  29 LQMYWTDHYLQWNASEYPGVKNVRFPDGQIWKPDILLYNSADerFDATFH-TNVLVNSSGHCQYLPPGIFKSSCYIDVRW 107

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38146010 154 FPFDQQNCTLTFSSFLYTVDSMLLDMEKevweiTDASRNIlqTHGEWELLGLSKataklSRGGNLYD-------QIVFYV 226
Cdd:cd19020 108 FPFDVQKCNLKFGSWTYGGWSLDLQMQE-----ADISGYI--SNGEWDLVGVPG-----KRNEKFYEcckepypDVTFTV 175

                ....*
gi 38146010 227 AIRRR 231
Cdd:cd19020 176 TMRRR 180