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 375298705   55 RPVTNiSVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV- 133
Cdd:TIGR00860  47 RPVFG-GPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDAr 125

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  134 --DKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVD--SMLLDMEKEVweitDASRNIL 209
Cdd:TIGR00860 126 fhGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNdiKLEWKEQGAV----QVDDSLF 201

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  210 QTHGEWELLGLSK---ATAKLSRGGnlYDQIVFYVAIRRRPSLYVINLLVPSGFLVAIDALSFYLPV-KSGNRVPFKITL 285
Cdd:TIGR00860 202 ISLPEFELLGVYGtryCTSETNTGE--YPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPAdASGARVSLGITT 279

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  286 LLGYNVFLLMMSDLLP-TSGTPLIGVYFALCLSLMVGSLLETIFITHLLHvatTQPPPLPRwlHSLLLHCnsPGRCCPTA 364
Cdd:TIGR00860 280 LLTMTTFSSGVRESLPaVSYVKAIDVYFAVCMAFVFLALLETAFVNYVHH---KDPAQGKR--HLLLERC--AWRLCKQE 352

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  365 PQKENKGPGLTPTHLPGVKEPEVSAGQ-------------MPGPAEAELTGGSEWTRAQREHEAQKQHSVE----LWLQF 427
Cdd:TIGR00860 353 PGEDYRRPALDHASLSSVEMRAKDGGRglespterqrllhSPPPAEGDLDLAGILEEVRIAHRFRKRDESEevvrDWKFR 432

                         410       420
                  ....*....|....*....|....*..
gi 375298705  428 SHAMDAMLFRLYLLFmasSIITVICLW 454
Cdd:TIGR00860 433 AKVIDKLSRMAFPLA---FLLFNIGYW 456

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 375298705   55 RPVTNiSVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV- 133
Cdd:TIGR00860  47 RPVFG-GPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDAr 125

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  134 --DKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVD--SMLLDMEKEVweitDASRNIL 209
Cdd:TIGR00860 126 fhGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNdiKLEWKEQGAV----QVDDSLF 201

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  210 QTHGEWELLGLSK---ATAKLSRGGnlYDQIVFYVAIRRRPSLYVINLLVPSGFLVAIDALSFYLPV-KSGNRVPFKITL 285
Cdd:TIGR00860 202 ISLPEFELLGVYGtryCTSETNTGE--YPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPAdASGARVSLGITT 279

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  286 LLGYNVFLLMMSDLLP-TSGTPLIGVYFALCLSLMVGSLLETIFITHLLHvatTQPPPLPRwlHSLLLHCnsPGRCCPTA 364
Cdd:TIGR00860 280 LLTMTTFSSGVRESLPaVSYVKAIDVYFAVCMAFVFLALLETAFVNYVHH---KDPAQGKR--HLLLERC--AWRLCKQE 352

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  365 PQKENKGPGLTPTHLPGVKEPEVSAGQ-------------MPGPAEAELTGGSEWTRAQREHEAQKQHSVE----LWLQF 427
Cdd:TIGR00860 353 PGEDYRRPALDHASLSSVEMRAKDGGRglespterqrllhSPPPAEGDLDLAGILEEVRIAHRFRKRDESEevvrDWKFR 432

                         410       420
                  ....*....|....*....|....*..
gi 375298705  428 SHAMDAMLFRLYLLFmasSIITVICLW 454
Cdd:TIGR00860 433 AKVIDKLSRMAFPLA---FLLFNIGYW 456

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 375298705   55 RPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV- 133
Cdd:pfam02931  17 RPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSDKIWKPDIVLYNKADGi 96

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  134 -DKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKE----VWEITDASRNI 208
Cdd:pfam02931  97 hEVTTPNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDDDppvvELEEIDLSDFW 176

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|.
gi 375298705  209 LQthGEWELLGLSKATAKLSRGG--NLYDQIVFYVAIRRRP 247
Cdd:pfam02931 177 LN--GEWDIVDVPAKRREYPYGCysELTGDVTFYFTLRRKP 215

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 375298705  31 NCSGFGQHGADPTALNSVFNRkPFRPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGI 110
Cdd:cd18996    1 NCSYYDVLKALNKTFNSLHLT-YTRPVKNWTPPTTVYLDLTLYAILDVDEKLQTLTTYIWLEMVWFNEFLSWNPEQFCGI 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 111 TKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSM 190
Cdd:cd18996   80 SKVSVPEDTLWKPDILIYEMTDKDKSPKIPYVYVSNNGTVRNYKPLQVVSTCSLDIYKFPFDTQNCNLTFSSFLHTVNDI 159

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 375298705 191 LLDMEKEVWEITDASRNILQTHGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRRR 246
Cdd:cd18996  160 ILNPGSNSEEITSESKEIFQTQGEWELLNIKVSDEKLSLLGNSFDQIVYQITIKRR 215

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 375298705  51 RKPFRPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIEL 130
Cdd:cd19011   13 KKGVRPVRDWRKPTTVSIDVMVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNVTQLSIPTDSIWVPDILINEF 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 131 MDVDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDsmllDMEKEVWEITDA---SRN 207
Cdd:cd19011   93 VDVGKSPEIPYVYVNHEGEVQNYKPIQVVTACSLDIYNFPFDVQNCSLTFTSWLHTIQ----DINISLWRSPEEvksDKS 168

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 375298705 208 ILQTHGEWELLG-LSKATAKLSRGGNLYDQIVFYVAIRRR 246
Cdd:cd19011  169 VFMNQGEWELLGvLPQYREFSIDISDSYAEMKFYVVIRRR 208

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 375298705 248 SLYVINLLVPSGFLVAIDALSFYLPVKSGNRVPFKITLLLGYNVFLLMMSDLLPTS--GTPLIGVYFALCLSLMVGSLLE 325
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATaiGTPLIGVYFVVCLALMVLSLLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 326 TIFITHLLHvattqppplprwlhslllhcnspgrccptapqkenkgpgltpthlpgvkepevsagqmpgpaeaeltggse 405
Cdd:cd19063   81 TILIVKLLH----------------------------------------------------------------------- 89

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|
gi 375298705 406 wtraqreheaqkqhsvelWLQFSHAMDAMLFRLYLLFMASSIITVICLWN 455
Cdd:cd19063   90 ------------------WLRVAYVLDRLLFRLYLLTVLAYAITLGLLWA 121

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 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFII-----ELMDVDKTPkgl 140
Cdd:cd18997    3 VTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYnnadgDFDSSYKTN--- 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 141 tAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDasrniLQTHGEWELLGl 220
Cdd:cd18997   80 -VIVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTVDLSD-----YIENGEWDLLG- 152

                        170       180       190
                 ....*....|....*....|....*....|.
gi 375298705 221 skATAKLSR-----GGNLYDQIVFYVAIRRR 246
Cdd:cd18997  153 --APAKRNVvkyscCPEPYPDVTFTIHIRRK 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 375298705  45 LNSVFNRKPFRPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPD 124
Cdd:cd19025    7 LGPSRYNKLIRPATNGSQLVTVQLMVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPD 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 125 IFIIELMD-VDKTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVweitd 203
Cdd:cd19025   87 VVLYNNADgMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLRSDV----- 161

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 375298705 204 ASRNILQTHGEWELLGLSKATAKlSRGGNLYDQIVFYVAIRRRP 247
Cdd:cd19025  162 ASLDDFTPSGEWDIVALPGRRNE-NPNDSTYVDITYDFIIRRKP 204

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 375298705  55 RPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDvd 134
Cdd:cd19032   18 RPVRNMSEPVEVNFGLALIQLINVDEKNQIMKTNVWLTMYWNDYQLKWDPADYGGIKVIRVPPDKVWKPDIVLFNNAD-- 95

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 135 ktPKGLTAYVSN-----EGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDM--EKEVWEITDASRN 207
Cdd:cd19032   96 --GNYEVSYKSNvliysTGEVLWVPPAIYKSSCTIDVEYFPFDQQECEMKFGSWTFNGDEVSLDLynNKKFVDLSDYWKS 173

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 375298705 208 ilqthGEWELLGLSKATAKLSRGGNLYDQIVFYVAIRRRP 247
Cdd:cd19032  174 -----GTWDIIDVPGQLVNKDDAGPTETDIIFKIKIRRKT 208

extracellular domain of nicotinic acetylcholine receptor subunit beta 1 (CHRNB1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 1 (beta1), encoded by the CHRNB1 gene. It is a muscle type subunit found predominantly in the neuromuscular junction (NMJ), but also in other tissues and cell lines such as adrenal glands, carcinomas, brain, and lung. Simultaneous mRNA and protein expression of beta1 nAChR subunit is present in human placenta and skeletal muscle. The beta1 nAChR subunit forms a heteropentamer with either (alpha1)2, gamma and delta subunits in embryonic type or (alpha1)2, epsilon and delta subunits in adult type receptors. nAChRs containing beta1 subunits have been attributed to efficient clustering and anchoring of the receptors to the cytoskeleton which is important for formation of synapses in the NMJ. Mutations in the transmembrane domain region of this gene are associated with slow-channel congenital myasthenic syndrome (CMS).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  55 RPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVD 134
Cdd:cd19024   17 RPARTVGDRVVVSVGLTLAQLISLNEKNEEMTTKVYLDLEWTDYRLSWDPAEYDGIDSLRITSDSVWLPDIVLMNNNDGN 96

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 135 -KTPKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLD-----MEKEVWEITdASRNI 208
Cdd:cd19024   97 fDVALDVNVLVSSDGSVRWHPPAIYRSSCSIEVTYFPFDWQNCSMVFRSYTYDSSEVSLQhgldpDGKELQEIV-IHENT 175

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 375298705 209 LQTHGEWELlgLSKATAKLSRGGN-LYDQIVFYVAIRRRP 247
Cdd:cd19024  176 FIENGQWSI--EHKPSRKNQLPGDpLYEDITFYLIIRRKP 213

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 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYV 144
Cdd:cd19027    3 IKLQLSLAQLISVNEREQIMTTNVWLNQEWTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNADGTYEVSVYTnAIV 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375298705 145 SNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYtvDSMLLDMekeVWEITDASRNILQTHGEWELLGL 220
Cdd:cd19027   83 QNNGSVAWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTY--DHTEIDM---VLKTPTASMDDFTPSGEWDIVAL 153

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 375298705  54 FRPVTNISVPTQVNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDV 133
Cdd:cd19022   16 LRPVEDTDKVLNVTLQITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDGLDSIRIPSNLVWRPDIVLYNKADD 95

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 134 DKT-PKGLTAYVSNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNIlqth 212
Cdd:cd19022   96 EFSePVNTNVVLRYDGKITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNGNQVDIINALDSGDLSDFVEDV---- 171

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 375298705 213 gEWELLGLSKATAKLSRG--GNLYDQIVFYVAIRRR 246
Cdd:cd19022  172 -EWEVHGMPAVKNVITYGccSEPYPDVTFTLILKRR 206

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 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLTAYV- 144
Cdd:cd19023    3 VTLQITLSQIIDMDERNQILTAYLWIRQVWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSMETNVVi 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 145 SNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRNIlqthgEWELLGLSKAT 224
Cdd:cd19023   83 RSDGQIMWDSPAITKSSCKVDVSFFPFDGQQCRLTFGSWTYNGNQIDILNLLDTGDLTDFVENV-----EWEVLGMPAKR 157

                        170       180
                 ....*....|....*....|....
gi 375298705 225 AKLSRG--GNLYDQIVFYVAIRRR 246
Cdd:cd19023  158 NVITYGccSEPYPDVTYTLLLKRR 181

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 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYV 144
Cdd:cd19019    3 VHFEVAITQLVNVDEVNQIMETNLWLRHIWNDYKLRWDPREYDGIEFMRVPADKIWKPDIVLYNNAVGDFQVEGKTkALL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 145 SNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLY---TVDSMLL----DMeKEVWEitdasrnilqtHGEWEL 217
Cdd:cd19019   83 KYNGMITWTPPAIFKSSCPMDITFFPFDHQNCSLKFGSWTYdkaKIDLLIIgskvDM-NDFWE-----------NSEWEI 150

                        170       180       190
                 ....*....|....*....|....*....|
gi 375298705 218 LGLS--KATAKLSRGGNLYDQIVFYVAIRR 245
Cdd:cd19019  151 VDASgyKHDIKYNCCEEIYTDITYSFYIRR 180

extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFIIELMDVDKTPKGLT-AYV 144
Cdd:cd19017    3 VRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWRPDIVLYNNADGDFAVTHLTkAHL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 145 SNEGRIRYKKPMKVDSICNLDIFYFPFDQQNCTLTFSSFLYTVDSM-LLDMEKEV-----WEitdasrnilqtHGEWELL 218
Cdd:cd19017   83 FHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFGSWTYDKAKIdLVSMHSRVdqldfWE-----------SGEWVIV 151

                        170       180
                 ....*....|....*....|....*....
gi 375298705 219 GL--SKATAKLSRGGNLYDQIVFYVAIRR 245
Cdd:cd19017  152 DAvgTYNTRKYECCAEIYPDITYAFIIRR 180

acetylcholine binding protein (AChBP); This family contains acetylcholine binding protein (AChBP) which is a soluble extracellular domain homolog secreted by protostomia, and has been widely recognized as a surrogate for the ligand binding domain of nicotinic acetylcholine receptors (nAChRs). AChBP forms a pentameric structure where the interfaces between the subunits provide an acetylcholine (ACh) binding pocket homologous to the binding pocket of nAChRs. Thus far, AChBPs have been characterized only in aquatic mollusks, which have shown low sensitivity to neonicotinoids, the insecticides targeting insect nAChRs. Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) which has been found in glial cells as a water-soluble protein modulating synaptic ACh concentration has its the binding pocket show better resemblance as it contains all the five aromatic residues fully conserved in nAChR. Five AChBP subunits have been characterized in Pardosa pseudoannulata, a predator enemy against rice insect pests, and share higher sequence similarities with nAChR subunits of both insects and mammals compared with mollusk AChBP subunits.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705  66 VNISFAMSAILDVNEQLHLLSSFLWLEMVWDNPFISWNPEECEGITKMSMAAKNLWLPDIFI---IELMDVDKTPKglTA 142
Cdd:cd18995    3 VSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAEYGNLKNLRLPSSKIWTPDIAVynsIGAPSVLFSPQ--LV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375298705 143 YVSNEGRIRYKKPMKVDSICNLDIFYfPFDQQNCTLTFSSFLYTVDSMLLDMEKEVWEITDASRnilqtHGEWELLglsK 222
Cdd:cd18995   81 LVSSDGTVLWVPPIRIRFSCDLDNVD-PEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYNQ-----SSKWELL---S 151

                        170       180
                 ....*....|....*....|....*....
gi 375298705 223 ATAKLSRGG-----NLYDQIVFYVAIRRR 246
Cdd:cd18995  152 ATQKREVKTysccpEPYPDIEFVFTFKKR 180