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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19030   1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVDDDGNTINKIDIDTAAFTENGEWAID 208
Cdd:cd19030  81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGMIRRYEGGSTEGPGETDVIYTLIIRRK 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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19030   1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVDDDGNTINKIDIDTAAFTENGEWAID 208
Cdd:cd19030  81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGMIRRYEGGSTEGPGETDVIYTLIIRRK 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 6752950    247 IIVPCVLISGLVLLAYFLPAQAGGQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVMNCVIVL 326
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGKYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950    327 NVSLRTPTTHATSPRLRQILLELLPRLLGSSPPPEDPrtaspaRRASSVGILLRAEELILKKPRSELVFEGQRHRHGTWT 406
Cdd:pfam02932  81 NVHHRSPSTHKMPPWVRKIFLEKLPRLLGMKRPPEAP------PPPASPGYGSKAEEYILRKPRSELPFEKQSERHGLGR 154

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 6752950    407 AALCQNLGA----------AAPEIRCCVDAVNFVAESTRDQEATGEELSDWVRMGKALDNVCFWAALVLFSVGSTLIF 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 6752950  241 LFYVINIIVPCVLISGLVLLAYFLPAQAGgQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVM 320
Cdd:cd19064   1 LFYTVNLIIPCVLISFLTVLVFYLPADSG-EKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSII 79

                        90
                ....*....|..
gi 6752950  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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19030   1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQFGVAYDANV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVDDDGNTINKIDIDTAAFTENGEWAID 208
Cdd:cd19030  81 LVYEGGSVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDDDGKTINKIDIDTEAYTENGEWAID 160

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGMIRRYEGGSTEGPGETDVIYTLIIRRK 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 6752950     24 ELSLYHHLFDNYDPECRPVRRPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSE 103
Cdd:pfam02931   1 EERLLDDLLSGYDKLVRPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950    104 HVWLPEIVLENNIDGQFGV-AYDSNVLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFav 182
Cdd:pfam02931  81 KIWKPDIVLYNKADGIHEVtTPNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRW-- 158

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 6752950    183 DDDGNTINKIDIDTAAFTENGEWAIDYCPGMIRRYEGGSTEGPgETDVIYTLIIRRKP 240
Cdd:pfam02931 159 DDDPPVVELEEIDLSDFWLNGEWDIVDVPAKRREYPYGCYSEL-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 6752950   24 ELSLYHHLFDNYDPECRPVRRPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSE 103
Cdd:cd19024   1 EGQLLEKLFENYNPKVRPARTVGDRVVVSVGLTLAQLISLNEKNEEMTTKVYLDLEWTDYRLSWDPAEYDGIDSLRITSD 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  104 HVWLPEIVLENNIDGQFGVAYDSNVLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVD 183
Cdd:cd19024  81 SVWLPDIVLMNNNDGNFDVALDVNVLVSSDGSVRWHPPAIYRSSCSIEVTYFPFDWQNCSMVFRSYTYDSSEVSLQHGLD 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 6752950  184 DDGNTINKIDIDTAAFTENGEWAIDYCPG-MIRRYEGGSTEgpgetDVIYTLIIRRKP 240
Cdd:cd19024 161 PDGKELQEIVIHENTFIENGQWSIEHKPSrKNQLPGDPLYE-----DITFYLIIRRKP 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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd18997   1 VNVTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSYKTNV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFifavdddgnTINKIDIDTAAFTENGEWAID 208
Cdd:cd18997  81 IVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDL---------QLKSDTVDLSDYIENGEWDLL 151

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGMIRRYEGGSTEGPgETDVIYTLIIRRK 239
Cdd:cd18997 152 GAPAKRNVVKYSCCPEP-YPDVTFTIHIRRK 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 6752950   27 LYHHLFD--NYDPECRPVRRPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEH 104
Cdd:cd19025   2 LVEHLLGpsRYNKLIRPATNGSQLVTVQLMVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWDPAEFDNMKKVRLPSKH 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  105 VWLPEIVLENNIDGQFGVAYDSNVLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFI----F 180
Cdd:cd19025  82 IWLPDVVLYNNADGMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDRTEIDLVlrsdV 161

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 6752950  181 AVDDDgntinkididtaaFTENGEWAIDYCPGmiRRyeggsTEGPGET---DVIYTLIIRRKP 240
Cdd:cd19025 162 ASLDD-------------FTPSGEWDIVALPG--RR-----NENPNDStyvDITYDFIIRRKP 204

extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19027   1 VSIKLQLSLAQLISVNEREQIMTTNVWLNQEWTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNADGTYEVSVYTNA 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVD----DDgntinkididtaaFTENGE 204
Cdd:cd19027  81 IVQNNGSVAWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDHTEIDMVLKTPtasmDD-------------FTPSGE 147

                       170       180       190
                ....*....|....*....|....*....|....*
gi 6752950  205 WAIDYCPGmiRRYEggSTEGPGETDVIYTLIIRRK 239
Cdd:cd19027 148 WDIVALPG--RRTV--NPLDPTYVDVTYDFIIKRK 178

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 6752950   24 ELSLYHHLFDNYDPECRPVRRPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSE 103
Cdd:cd19015   1 EDRLFKHLFTGYNRWSRPVPNTSDVVIVKFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKLRWNPTDFDNVTSIRVPSE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  104 HVWLPEIVLENNIDGQFGVAYDSNVLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVefifavd 183
Cdd:cd19015  81 MIWIPDIVLYNNADGEFAVTHMTKAHLFSTGKVKWVPPAIYKSSCSIDVTFFPFDQQNCKMKFGSWTYDKAKI------- 153

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 6752950  184 dDGNTINKiDIDTAAFTENGEWAIDYCPGMI--RRYEGGSTEGPgetDVIYTLIIRRKP 240
Cdd:cd19015 154 -DLEQMEQ-TVDLKDYWESGEWAIVNATGTYnsKKYDCCTEIYP---DITYYFVIRRLP 207

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 6752950   27 LYHHLFDNYDPECRPVRRPEDTVTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVW 106
Cdd:cd19022   4 LFNDLFEDYSNALRPVEDTDKVLNVTLQITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDGLDSIRIPSNLVW 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  107 LPEIVLENNIDGQFGVAYDSNVLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVDDDg 186
Cdd:cd19022  84 RPDIVLYNKADDEFSEPVNTNVVLRYDGKITWDAPAITKSSCVVDVSYFPFDNQQCNLTFGSWTYNGNQVDIINALDSG- 162

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|...
gi 6752950  187 ntinkidiDTAAFTENGEWAIDYCPGMIRRYEGGSTEGPgETDVIYTLIIRRK 239
Cdd:cd19022 163 --------DLSDFVEDVEWEVHGMPAVKNVITYGCCSEP-YPDVTFTLILKRR 206

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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDG-QFGVAYDSN 127
Cdd:cd18989   1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSlDLLGDSNTL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  128 VLVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFavdddgntiNKIDIDTAAFTENGEWAI 207
Cdd:cd18989  81 VRVSSDGTVTWVPPGVLTTSCDIDVTYFPFDTQTCSLRFGSWSYTTDEINLTP---------SSNGVDLEDYEENGEWEL 151

                       170       180       190
                ....*....|....*....|....*....|..
gi 6752950  208 DycpGMIRRYEGGSTEGPGETDVIYTLIIRRK 239
Cdd:cd18989 152 L---STSVSREEDKYCNETYSELTFTITLKRR 180

extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19023   1 LNVTLQITLSQIIDMDERNQILTAYLWIRQVWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSMETNV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFIFAVDDDgntinkidiDTAAFTENGEWAID 208
Cdd:cd19023  81 VIRSDGQIMWDSPAITKSSCKVDVSFFPFDGQQCRLTFGSWTYNGNQIDILNLLDTG---------DLTDFVENVEWEVL 151

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGMIRRYEGGSTEGPgETDVIYTLIIRRK 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 6752950  241 LFYVINIIVPCVLISGLVLLAYFLPAQAGgQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRYLIFVMVVATLIVM 320
Cdd:cd19064   1 LFYTVNLIIPCVLISFLTVLVFYLPADSG-EKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSII 79

                        90
                ....*....|..
gi 6752950  321 NCVIVLNVSLRT 332
Cdd:cd19064  80 VTVIVLNVHHRV 91

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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd03558   1 VTVTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFYNNKDADFVTTDNVLI 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEfiFAVDDDgntinkiDIDTAAFTENGEWAID 208
Cdd:cd03558  81 RLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIE--LVWDSE-------RPDQADFLELPEWDIV 151

                       170       180       190
                ....*....|....*....|....*....|.
gi 6752950  209 YCPGmirRYEGGSTEGPGETDVIYTLIIRRK 239
Cdd:cd03558 152 EKRG---RYCTVVYNTGIYSDITYRFRLKRQ 179

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 6752950   49 VTITLKVTLTNLISLNEKEETLTTSVWIGIDWHDYRLNYSKDDFAGVGILRVPSEHVWLPEIVLENNIDGQFGVAYDSNV 128
Cdd:cd19020   2 LTVYFSLSLMQIMDVDEKNQVLTTNIWLQMYWTDHYLQWNASEYPGVKNVRFPDGQIWKPDILLYNSADERFDATFHTNV 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6752950  129 LVYEGGYVSWLPPAIYRSTCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEfifavdddgntINKIDIDTAAFTENGEWAID 208
Cdd:cd19020  82 LVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQKCNLKFGSWTYGGWSLD-----------LQMQEADISGYISNGEWDLV 150

                       170       180       190
                ....*....|....*....|....*....|....*
gi 6752950  209 YCPGmiRR----YEGGSTEGPgetDVIYTLIIRRK 239
Cdd:cd19020 151 GVPG--KRnekfYECCKEPYP---DVTFTVTMRRR 180