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 1953403383   1 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 80
Cdd:cd19025    31 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  81 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRNENPDDST 160
Cdd:cd19025   111 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLRSDVASLDDFTPSGEWDIVALPGRRNENPNDST 190

                         170
                  ....*....|....
gi 1953403383 161 YVDITYDFIIRRKP 174
Cdd:cd19025   191 YVDITYDFIIRRKP 204

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 1953403383   1 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 80
Cdd:cd19025    31 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  81 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRNENPDDST 160
Cdd:cd19025   111 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLRSDVASLDDFTPSGEWDIVALPGRRNENPNDST 190

                         170
                  ....*....|....
gi 1953403383 161 YVDITYDFIIRRKP 174
Cdd:cd19025   191 YVDITYDFIIRRKP 204

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFY-SNAVVSYD 80
Cdd:pfam02931  32 LYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSDKIWKPDIVLYNKADGIHEVTTPnTNVRVYYD 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  81 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVA-------SLDDFTPSGEWDIVALPGRRN 153
Cdd:pfam02931 112 GTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDDDPPvveleeiDLSDFWLNGEWDIVDVPAKRR 191

                         170       180
                  ....*....|....*....|....
gi 1953403383 154 ENPDDST---YVDITYDFIIRRKP 174
Cdd:pfam02931 192 EYPYGCYselTGDVTFYFTLRRKP 215

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383 175 LFYTINLIIPCVLITSLAILVFYLPSDCGEKMTLCISVLLALTVFLLLISKIVPPTSLDVPLVGKYLMFTMVLVTFSIVT 254
Cdd:cd19064     1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                          90
                  ....*....|
gi 1953403383 255 SVCVLNVHHR 264
Cdd:cd19064    81 TVIVLNVHHR 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 1953403383   1 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 80
Cdd:cd19025    31 MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYD 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  81 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRNENPDDST 160
Cdd:cd19025   111 GSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLRSDVASLDDFTPSGEWDIVALPGRRNENPNDST 190

                         170
                  ....*....|....
gi 1953403383 161 YVDITYDFIIRRKP 174
Cdd:cd19025   191 YVDITYDFIIRRKP 204

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd18997     7 LTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSYKTNVIVYSDG 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRNENPDDS-- 159
Cdd:cd18997    87 TVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTVDLSDYIENGEWDLLGAPAKRNVVKYSCcp 166

                         170
                  ....*....|....*
gi 1953403383 160 -TYVDITYDFIIRRK 173
Cdd:cd18997   167 ePYPDVTFTIHIRRK 181

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSY-- 79
Cdd:TIGR00860  61 LFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDARFHGITMTNVLVRIhp 140

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  80 DGSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVA---SLDDFTPSGEWDIVALPGRRNENP 156
Cdd:TIGR00860 141 NGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKLEWKEQGAvqvDDSLFISLPEFELLGVYGTRYCTS 220

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383 157 DDST--YVDITYDFIIRRKPLFYTINLIIPCVLITSLAILVFYLPSDC-GEKMTLCISVLLALTVFLLLISKIVPPTSLd 233
Cdd:TIGR00860 221 ETNTgeYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADAsGARVSLGITTLLTMTTFSSGVRESLPAVSY- 299

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383 234 VPLVGKYLMFTMVLVTFSIVTSVCVLNVHHRSPTTHTMapwvkVVFLEKLPTLLFMQQP---RHRCARQRLRLRRRQRER 310
Cdd:TIGR00860 300 VKAIDVYFAVCMAFVFLALLETAFVNYVHHKDPAQGKR-----HLLLERCAWRLCKQEPgedYRRPALDHASLSSVEMRA 374

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383 311 EAGALLFrEAPGESYSGSaRGGVGTDGCGLRSAVDGVRFIADHVRNEDDDQSVSEDWKYVAMVIDRLFLWIFVFVCVFGT 390
Cdd:TIGR00860 375 KDGGRGL-ESPTERQRLL-HSPPPAEGDLDLAGILEEVRIAHRFRKRDESEEVVRDWKFRAKVIDKLSRMAFPLAFLLFN 452

                  ....*
gi 1953403383 391 IGMFL 395
Cdd:TIGR00860 453 IGYWM 457

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 1953403383   4 LAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDGSI 83
Cdd:cd19031    36 LSQLIDVDEKNQIMTTNVWLEQEWYDYKLVWDPAEYGGVEMLYVPSEDIWLPDIVLYNNADGNYEVTLMTKATLHYNGTV 115

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  84 FWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDL-----------VLKSDVASLDDFTPSGEWDIVALPGRR 152
Cdd:cd19031   116 RWEPPAIYKSSCEIDVEYFPFDEQTCFMKFGSWTYDGFEVDLrhvdqkygsedEVIDVGIDLSEFYPSVEWDLLEVPARR 195

                         170       180
                  ....*....|....*....|....*..
gi 1953403383 153 NEN--PD-DSTYVDITYDFIIRRKPLF 176
Cdd:cd19031   196 NEKyyPCcDEPYPDITFNITLRRKTLF 222

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19032    33 LALIQLINVDEKNQIMKTNVWLTMYWNDYQLKWDPADYGGIKVIRVPPDKVWKPDIVLFNNADGNYEVSYKSNVLIYSTG 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLD--DFTPSGEWDIVALPGRRNENPDDS 159
Cdd:cd19032   113 EVLWVPPAIYKSSCTIDVEYFPFDQQECEMKFGSWTFNGDEVSLDLYNNKKFVDlsDYWKSGTWDIIDVPGQLVNKDDAG 192

                         170
                  ....*....|....*.
gi 1953403383 160 -TYVDITYDFIIRRKP 174
Cdd:cd19032   193 pTETDIIFKIKIRRKT 208

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19033     7 LQLIQILDLDENNQVLTTNVWSRYRWTDYHLRWNPEDYGGVTHVRIPPDKIWTPDIKLYNYADERLEERREAMVVVYSTG 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDV--ASLDDFTPSGEWDIVALPGRRNE--NPD 157
Cdd:cd19033    87 TVLWMPQAIYKSTCEIDIKYFPFDTQTCYLKFGSWTYDGTRLDITFYDNEeeIDLTDYIESNEWEILAYPAVKNVkyYPC 166

                         170
                  ....*....|....*..
gi 1953403383 158 -DSTYVDITYDFIIRRK 173
Cdd:cd19033   167 cPEPYPDLTFFLVIKRR 183

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19016    32 VSMSQLVKVDEVNQIMETNLWLKHIWNDYKLKWNPSDYGGAEFMRVPAEKIWKPDIVLYNNAVGDFQVDDKTKALLKYTG 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRNE---NPDD 158
Cdd:cd19016   112 EVTWIPPAIFKSSCKIDVTYFPFDYQNCTMKFGSWSYDKAKIDLVLIGSSMNLKDYWESGEWAIIKAPGYKHDikyNCCE 191

                         170
                  ....*....|....*.
gi 1953403383 159 STYVDITYDFIIRRKP 174
Cdd:cd19016   192 EIYPDITYSLYIRRLP 207

extracellular domain of nicotinic acetylcholine receptor subunit gamma (CHRNG); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit gamma (gamma), encoded by the CHRNG gene expressed during early fetal development, and replaced by the epsilon subunit in the adult. The gamma subunit forms a heteropentamer with (alpha1)2, beta, and delta and plays a role in neuromuscular organogenesis and ligand binding. Disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in CHRNG may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome (MPS), a condition characterized by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383   3 SLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDGS 82
Cdd:cd19029    10 TLTNLISLNEKEEALTTNVWIEIQWNDYRLRWNPSEYEGIWVLRVPSTMVWLPDIVLENNIDGQFEVAYYANVLVYPDGS 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  83 IFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASL--------DDFTPSGEWDIVALPGRRNE 154
Cdd:cd19029    90 MYWLPPAIYRSTCPIEVTYFPFDWQNCSLVFQSQTYSANEINLQLSVEEGTTiewididpEAFTENGEWAIRHRPAKKIL 169

                         170       180
                  ....*....|....*....|....
gi 1953403383 155 NP----DDSTYVDITYDFIIRRKP 174
Cdd:cd19029   170 NPqlpkDDLGYQEIVFYLIIQRKP 193

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19028    33 LTLSNLISLKEVDETLTTNVWVEHGWYDHRLTWNASEYGNISILRLPPEMVWLPEIVLENNNDGQFEVAYYCNVLVYSDG 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSD------------VASLDDFTPSGEWDIVALP 149
Cdd:cd19028   113 FVYWLPPAIFRSSCPINVNYFPFDWQNCSLKFSSLNYNAKEINLDLKTDtddgktypvewiIIDPEGFTENGEWEIVHKP 192

                         170       180
                  ....*....|....*....|....*....
gi 1953403383 150 GRRN----ENPDDSTYVDITYDFIIRRKP 174
Cdd:cd19028   193 AKKNidpsKPPESTKYQDITFYLIIKRKP 221

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19017     7 LSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWRPDIVLYNNADGDFAVTHLTKAHLFHDG 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLV-LKSDVASLdDFTPSGEWDIVALPGRRNENPDD-- 158
Cdd:cd19017    87 RVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFGSWTYDKAKIDLVsMHSRVDQL-DFWESGEWVIVDAVGTYNTRKYEcc 165

                         170
                  ....*....|....*
gi 1953403383 159 -STYVDITYDFIIRR 172
Cdd:cd19017   166 aEIYPDITYAFIIRR 180

extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (CHRNA1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (alpha1), encoded by the CHRNA1 gene. These muscle type nicotinic subunits form heteropentamers with other nAChR subunits, most broadly expressed as combination of two alpha1, beta1, delta, and epsilon subunits in mature muscles, and of two alpha1, beta1, delta, and gamma in embryonic cells. The alpha1 subunit in human nAChR is the primary target of Myasthenia gravis antibodies that disrupt communication between the nervous system and the muscle, causing chronic muscle weakness.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383   4 LAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDGSI 83
Cdd:cd19014    36 LIQLINVDEVNQIVTTNVRLKQQWIDVNLKWNPDDYGGIKKIRIPSSDIWRPDLVLYNNADGDFAIVKETKVLLEYTGKI 115

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  84 FWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRN----ENPDDS 159
Cdd:cd19014   116 TWTPPAIFKSYCEIIVTHFPFDQQNCSMKLGTWTYDGTLVVINPESDRPDLSNFMESGEWVMKDYRGWKHwvyyTCCPDT 195

                         170
                  ....*....|....*
gi 1953403383 160 TYVDITYDFIIRRKP 174
Cdd:cd19014   196 PYLDITYHFLLQRLP 210

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19020     8 LSLMQIMDVDEKNQVLTTNIWLQMYWTDHYLQWNASEYPGVKNVRFPDGQIWKPDILLYNSADERFDATFHTNVLVNSSG 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSdvASLDDFTPSGEWDIVALPGRRNENPDD--- 158
Cdd:cd19020    88 HCQYLPPGIFKSSCYIDVRWFPFDVQKCNLKFGSWTYGGWSLDLQMQE--ADISGYISNGEWDLVGVPGKRNEKFYEcck 165

                         170
                  ....*....|....*
gi 1953403383 159 STYVDITYDFIIRRK 173
Cdd:cd19020   166 EPYPDVTFTVTMRRR 180

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 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19022    32 ITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDGLDSIRIPSNLVWRPDIVLYNKADDEFSEPVNTNVVLRYDG 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSDVASLDDFTPSGEWDIVALPGRRN-------E 154
Cdd:cd19022   112 KITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNGNQVDIINALDSGDLSDFVEDVEWEVHGMPAVKNvitygccS 191

                         170
                  ....*....|....*....
gi 1953403383 155 NPddstYVDITYDFIIRRK 173
Cdd:cd19022   192 EP----YPDVTFTLILKRR 206

extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383   2 VSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLYNNADGMYEVSFYSNAVVSYDG 81
Cdd:cd19021     7 LSLLQIIDVDEKNQVLITNAWLQMYWVDIYLSWDQYEYPGVQNLRFPSDQIWVPDILLYNSADERFDATFHTNVLVNYSG 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953403383  82 SIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDRTEIDLVLKSdvASLDDFTPSGEWDIVALPGRRNENPDD--- 158
Cdd:cd19021    87 SCQYIPPGILKSTCYIDVRWFPFDVQKCDLKFGSWTHSGWLIDLQMLE--ADISNYISNGEWDLVGVPGKRNELYYEcck 164

                         170
                  ....*....|....*
gi 1953403383 159 STYVDITYDFIIRRK 173
Cdd:cd19021   165 EPYPDVTYTITMRRR 179