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 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd19030    1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNGGEDISKIDIDTEAYTENGEWAID 208
Cdd:cd19030   81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPGVIRHHNAGSADGPGNTDVLYSLIIRRK 239
Cdd:cd19030  161 FCPGVIRRHHGGSTDGPGETDVIYSLIIRRK 191

extracellular domain of nicotinic acetylcholine receptor subunit epsilon (CHRNE); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit epsilon (epsilon), encoded by the CHRNE gene and found in adult skeletal muscle. Epsilon subunit forms a heteropentamer with (alpha1)2, beta and delta after birth, replacing the gamma subunit seen in embryonic receptors. The adult-type epsilon-AChR has a higher conductance and a shorter open time compared to embryonic gamma-AChR and the open channel is non-selectively cation permeable. Mutations of the CHRNE gene are the most common causes of congenital myasthenic syndrome (CMS), most of which are autosomal recessive loss-of-function mutations, resulting in endplate AChR deficiency. A highly fatal fast-channel syndrome is caused by AChR epsilon subunit mutation (Trp to Arg; changing environment from anionic to cationic) at the agonist binding site at the alpha/epsilon interface of the receptor, thus disrupting agonist binding affinity and gating efficiency.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd19030    1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNGGEDISKIDIDTEAYTENGEWAID 208
Cdd:cd19030   81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPGVIRHHNAGSADGPGNTDVLYSLIIRRK 239
Cdd:cd19030  161 FCPGVIRRHHGGSTDGPGETDVIYSLIIRRK 191

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 560990960  247 IIVPCVLISGLVLLAYFLPAQAGGQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVMNCVIVL 326
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGKYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  327 NVSLRTPTTHVMSPRLRHVLLELLPRLLGWGLPPEVPPAASPPRRASslglllRAEELILKKPRSELVFEGQRHRHGTWT 406
Cdd:pfam02932  81 NVHHRSPSTHKMPPWVRKIFLEKLPRLLGMKRPPEAPPPPASPGYGS------KAEEYILRKPRSELPFEKQSERHGLGR 154

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 560990960  407 AVLCQSLGA----------AAPEIRCCVDAVNFVAESTRDQETTGEEVSDWVRMGKALDNVCFWAALVLFLLGSSLIF 474
Cdd:pfam02932 155 ETTCSYGCSlgngssqpreLSPELKKAVEGVNFIAKHLRSQDEYISVKEDWKYVAMVIDRLSRWIFPIAFVLGTLGYF 232

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 560990960 241 LFYVINIIVPCVLISGLVLLAYFLPAQAGgQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVM 320
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSG-EKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSII 79

                         90
                 ....*....|..
gi 560990960 321 NCVIVLNVSLRT 332
Cdd:cd19064   80 VTVIVLNVHHRV 91

extracellular domain of nicotinic acetylcholine receptor subunit epsilon (CHRNE); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit epsilon (epsilon), encoded by the CHRNE gene and found in adult skeletal muscle. Epsilon subunit forms a heteropentamer with (alpha1)2, beta and delta after birth, replacing the gamma subunit seen in embryonic receptors. The adult-type epsilon-AChR has a higher conductance and a shorter open time compared to embryonic gamma-AChR and the open channel is non-selectively cation permeable. Mutations of the CHRNE gene are the most common causes of congenital myasthenic syndrome (CMS), most of which are autosomal recessive loss-of-function mutations, resulting in endplate AChR deficiency. A highly fatal fast-channel syndrome is caused by AChR epsilon subunit mutation (Trp to Arg; changing environment from anionic to cationic) at the agonist binding site at the alpha/epsilon interface of the receptor, thus disrupting agonist binding affinity and gating efficiency.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd19030    1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNGGEDISKIDIDTEAYTENGEWAID 208
Cdd:cd19030   81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPGVIRHHNAGSADGPGNTDVLYSLIIRRK 239
Cdd:cd19030  161 FCPGVIRRHHGGSTDGPGETDVIYSLIIRRK 191

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 560990960   24 ELRLYHHLLDNYDPGRRPVQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSE 103
Cdd:pfam02931   1 EERLLDDLLSGYDKLVRPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  104 LVWLPEIVLENNIDGQFGV-AYAANVLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAK 182
Cdd:pfam02931  81 KIWKPDIVLYNKADGIHEVtTPNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDD 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 560990960  183 DNggEDISKIDIDTEAYTENGEWAIDFCPGVIRHHNAGSADGPgNTDVLYSLIIRRKP 240
Cdd:pfam02931 161 DP--PVVELEEIDLSDFWLNGEWDIVDVPAKRREYPYGCYSEL-TGDVTFYFTLRRKP 215

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 560990960  24 ELRLYHHLLDNYDPGRRPVQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSE 103
Cdd:cd19024    1 EGQLLEKLFENYNPKVRPARTVGDRVVVSVGLTLAQLISLNEKNEEMTTKVYLDLEWTDYRLSWDPAEYDGIDSLRITSD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 104 LVWLPEIVLENNIDGQFGVAYAANVLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKD 183
Cdd:cd19024   81 SVWLPDIVLMNNNDGNFDVALDVNVLVSSDGSVRWHPPAIYRSSCSIEVTYFPFDWQNCSMVFRSYTYDSSEVSLQHGLD 160

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 184 NGGEDISKIDIDTEAYTENGEWaidfcpgVIRHHNA---GSADGPGNTDVLYSLIIRRKP 240
Cdd:cd19024  161 PDGKELQEIVIHENTFIENGQW-------SIEHKPSrknQLPGDPLYEDITFYLIIRRKP 213

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 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd18997    1 VNVTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSYKTNV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNggediskidIDTEAYTENGEWAID 208
Cdd:cd18997   81 IVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDT---------VDLSDYIENGEWDLL 151

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPgVIRHHNAGSADGPGNTDVLYSLIIRRK 239
Cdd:cd18997  152 GAP-AKRNVVKYSCCPEPYPDVTFTIHIRRK 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 560990960  26 RLYHHLLD--NYDPGRRPVQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSE 103
Cdd:cd19025    1 RLVEHLLGpsRYNKLIRPATNGSQLVTVQLMVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSK 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 104 LVWLPEIVLENNIDGQFGVAYAANVLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAkd 183
Cdd:cd19025   81 HIWLPDVVLYNNADGMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVLR-- 158

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 560990960 184 nggEDISKIDidteAYTENGEWAIDFCPGViRHHNAGSAdgpGNTDVLYSLIIRRKP 240
Cdd:cd19025  159 ---SDVASLD----DFTPSGEWDIVALPGR-RNENPNDS---TYVDITYDFIIRRKP 204

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 560990960  26 RLYHHLLDNYDPGRRP-VQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSEL 104
Cdd:cd19031    4 RLYDDLLSNYNYNRRPrVTNDSDTLTVKLGLKLSQLIDVDEKNQIMTTNVWLEQEWYDYKLVWDPAEYGGVEMLYVPSED 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 105 VWLPEIVLENNIDGQFGVAYAANVLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDN 184
Cdd:cd19031   84 IWLPDIVLYNNADGNYEVTLMTKATLHYNGTVRWEPPAIYKSSCEIDVEYFPFDEQTCFMKFGSWTYDGFEVDLRHVDQK 163

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 185 GGEDISKID--IDTEAYTENGEWAIDFCPGVIRHHNAGSADGPgNTDVLYSLIIRRKPLF 242
Cdd:cd19031  164 YGSEDEVIDvgIDLSEFYPSVEWDLLEVPARRNEKYYPCCDEP-YPDITFNITLRRKTLF 222

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  24 ELRLYHHLLDNYDPGRRPVQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSE 103
Cdd:cd19015    1 EDRLFKHLFTGYNRWSRPVPNTSDVVIVKFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKLRWNPTDFDNVTSIRVPSE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 104 LVWLPEIVLENNIDGQFGVAYAANVLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFvfakd 183
Cdd:cd19015   81 MIWIPDIVLYNNADGEFAVTHMTKAHLFSTGKVKWVPPAIYKSSCSIDVTFFPFDQQNCKMKFGSWTYDKAKIDL----- 155

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 560990960 184 nggEDISKiDIDTEAYTENGEWAIDFCPGVirhHNAGSADGPGNT--DVLYSLIIRRKP 240
Cdd:cd19015  156 ---EQMEQ-TVDLKDYWESGEWAIVNATGT---YNSKKYDCCTEIypDITYYFVIRRLP 207

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  24 ELRLYHHLLDNYDPGRRPVQKPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSE 103
Cdd:cd19018    3 EDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVPSD 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 104 LVWLPEIVLENNIDGQFGVAYAANVLISDGGyVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFakd 183
Cdd:cd19018   83 SIWIPDIVLYDNADGRFEGTSTKTVVRYDGT-ITWTPPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIIL--- 158

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 560990960 184 nggEDiskIDIDTEAYTENGEWAIDFCPGVIRHHNAGSADGPGNTdvlYSLIIRRKPL 241
Cdd:cd19018  159 ---ED---YDVDKRDFFDNGEWEIVSATGSKGNRTDGCCWYPFIT---YSFIIRRLPL 207

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 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDG-QFGVAYAAN 127
Cdd:cd18989    1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSlDLLGDSNTL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 128 VLISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNggediskidIDTEAYTENGEWAI 207
Cdd:cd18989   81 VRVSSDGTVTWVPPGVLTTSCDIDVTYFPFDTQTCSLRFGSWSYTTDEINLTPSSNG---------VDLEDYEENGEWEL 151

                        170       180       190
                 ....*....|....*....|....*....|..
gi 560990960 208 DfcpGVIRHHNAGSADGPGNTDVLYSLIIRRK 239
Cdd:cd18989  152 L---STSVSREEDKYCNETYSELTFTITLKRR 180

extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd03558    1 VTVTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFYNNKDADFVTTDNVLI 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVfakdNGGEDISKIDidteaYTENGEWAID 208
Cdd:cd03558   81 RLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIELV----WDSERPDQAD-----FLELPEWDIV 151

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPGviRHHNAGSADGPgNTDVLYSLIIRRK 239
Cdd:cd03558  152 EKRG--RYCTVVYNTGI-YSDITYRFRLKRQ 179

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 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd19023    1 LNVTLQITLSQIIDMDERNQILTAYLWIRQVWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSMETNV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKDNGgediskidiDTEAYTENGEWAID 208
Cdd:cd19023   81 VIRSDGQIMWDSPAITKSSCKVDVSFFPFDGQQCRLTFGSWTYNGNQIDILNLLDTG---------DLTDFVENVEWEVL 151

                        170       180       190
                 ....*....|....*....|....*....|.
gi 560990960 209 FCPGVIRHHNAGSADGPgNTDVLYSLIIRRK 239
Cdd:cd19023  152 GMPAKRNVITYGCCSEP-YPDVTYTLLLKRR 181

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 560990960 241 LFYVINIIVPCVLISGLVLLAYFLPAQAGgQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVM 320
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSG-EKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSII 79

                         90
                 ....*....|..
gi 560990960 321 NCVIVLNVSLRT 332
Cdd:cd19064   80 VTVIVLNVHHRV 91

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 560990960  49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFGGVEILRVPSELVWLPEIVLENNIDGQFGVAYAANV 128
Cdd:cd19019    1 VTVHFEVAITQLVNVDEVNQIMETNLWLRHIWNDYKLRWDPREYDGIEFMRVPADKIWKPDIVLYNNAVGDFQVEGKTKA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 560990960 129 LISDGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFVFAKdnggediSKIDIDTeaYTENGEWAID 208
Cdd:cd19019   81 LLKYNGMITWTPPAIFKSSCPMDITFFPFDHQNCSLKFGSWTYDKAKIDLLIIG-------SKVDMND--FWENSEWEIV 151

                        170       180       190
                 ....*....|....*....|....*....|
gi 560990960 209 FCPGvIRHHNAGSADGPGNTDVLYSLIIRR 238
Cdd:cd19019  152 DASG-YKHDIKYNCCEEIYTDITYSFYIRR 180