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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVL-SPQIA 105
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAEYGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLfSPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVTHDGSVMFIPAQRLSFMCDPTGVDSEEGVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQVQH 185
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYNQSSKWELLSATQKREVKT 160

                       170       180
                ....*....|....*....|
2Y7Y_B      186 YSCCPEPYIDVNLVVKFRER 205
Cdd:cd18995 161 YSCCPEPYPDIEFVFTFKKR 180

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVL-SPQIA 105
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAEYGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLfSPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVTHDGSVMFIPAQRLSFMCDPTGVDSEEGVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQVQH 185
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYNQSSKWELLSATQKREVKT 160

                       170       180
                ....*....|....*....|
2Y7Y_B      186 YSCCPEPYIDVNLVVKFRER 205
Cdd:cd18995 161 YSCCPEPYPDIEFVFTFKKR 180

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B         22 TKDDPLTVTLGFTLQDIVKVDsstnEVDLVY----YEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSS--TR 95
Cdd:TIGR00860  50 FGGPPVTVSFNLFLRSIMDVD----EKNMDYttniWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEkdAR 125

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B         96 PVQVLSPQIAVVTH-DGSVMF-IPAQ-RLSFMCD----PTGVDseegvTCAVKFGSWVYSGFEIDL---KTDTDQVDLSS 165
Cdd:TIGR00860 126 FHGITMTNVLVRIHpNGSVLYsPRITlTLACPMDlrnfPFDVQ-----NCSLKFESWGYTTNDIKLewkEQGAVQVDDSL 200

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|
2Y7Y_B        166 YYASSKYEILSATQTRQvQHYSCCPEPYIDVNLVVKFRER 205
Cdd:TIGR00860 201 FISLPEFELLGVYGTRY-CTSETNTGEYPCLTFSFVLRRR 239

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVL-SPQIA 105
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAEYGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLfSPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVTHDGSVMFIPAQRLSFMCDPTGVDSEEGVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQVQH 185
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYNQSSKWELLSATQKREVKT 160

                       170       180
                ....*....|....*....|
2Y7Y_B      186 YSCCPEPYIDVNLVVKFRER 205
Cdd:cd18995 161 YSCCPEPYPDIEFVFTFKKR 180

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVL--SPQI 104
Cdd:cd18989   1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSLDLLgdSNTL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      105 AVVTHDGSVMFIPAQRLSFMCDPTG----VDSeegVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQT 180
Cdd:cd18989  81 VRVSSDGTVTWVPPGVLTTSCDIDVtyfpFDT---QTCSLRFGSWSYTTDEINLTPSSNGVDLEDYEENGEWELLSTSVS 157

                       170       180
                ....*....|....*....|....*.
2Y7Y_B      181 RQVQHYscCPEPYIDVNLVVKFReRR 206
Cdd:cd18989 158 REEDKY--CNETYSELTFTITLK-RR 180

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B        6 RLKSDLFNRSP--MYPGPTKD-DPLTVTLGFTLQDIVKVDS-----STNevdlVYYEQQrWKLNSLMWDPNEYGNITDFR 77
Cdd:cd19031   4 RLYDDLLSNYNynRRPRVTNDsDTLTVKLGLKLSQLIDVDEknqimTTN----VWLEQE-WYDYKLVWDPAEYGGVEMLY 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       78 TSAADIWTPDITAY----------SSTRpvqvlspqiAVVTHDGSVMFIPAQRLSFMCDptgVDSE----EGVTCAVKFG 143
Cdd:cd19031  79 VPSEDIWLPDIVLYnnadgnyevtLMTK---------ATLHYNGTVRWEPPAIYKSSCE---IDVEyfpfDEQTCFMKFG 146

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....
2Y7Y_B      144 SWVYSGFEIDLK---TDTDQ--------VDLSSYYASSKYEILSATQTRQVQHYSCCPEPYIDV 196
Cdd:cd19031 147 SWTYDGFEVDLRhvdQKYGSedevidvgIDLSEFYPSVEWDLLEVPARRNEKYYPCCDEPYPDI 210

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       19 PGPTKDDPLTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTR-PV 97
Cdd:cd19015  18 PVPNTSDVVIVKFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKLRWNPTDFDNVTSIRVPSEMIWIPDIVLYNNADgEF 97

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       98 QVLSPQIAVVTHDGSVMFIPAQRLSFMC--DPTGVDSEEGvTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEIL 175
Cdd:cd19015  98 AVTHMTKAHLFSTGKVKWVPPAIYKSSCsiDVTFFPFDQQ-NCKMKFGSWTYDKAKIDLEQMEQTVDLKDYWESGEWAIV 176

                       170       180
                ....*....|....*....|.
2Y7Y_B      176 SATQTRQVQHYSCCPEPYIDV 196
Cdd:cd19015 177 NATGTYNSKKYDCCTEIYPDI 197

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSStNEVDLVY-YEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVLSPQIA 105
Cdd:cd19023   1 LNVTLQITLSQIIDMDER-NQILTAYlWIRQVWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSMETN 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVT-HDGSVMF-IPAQRLSFMCDPTGVDSEEGVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQV 183
Cdd:cd19023  80 VVIrSDGQIMWdSPAITKSSCKVDVSFFPFDGQQCRLTFGSWTYNGNQIDILNLLDTGDLTDFVENVEWEVLGMPAKRNV 159

                       170       180
                ....*....|....*....|..
2Y7Y_B      184 QHYSCCPEPYIDVNLVVKFRER 205
Cdd:cd19023 160 ITYGCCSEPYPDVTYTLLLKRR 181

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       26 PLTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTRPVQVLSPQIA 105
Cdd:cd19020   1 PLTVYFSLSLMQIMDVDEKNQVLTTNIWLQMYWTDHYLQWNASEYPGVKNVRFPDGQIWKPDILLYNSADERFDATFHTN 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 V-VTHDGSVMFIPAQRLSFMCD------PTGVDSeegvtCAVKFGSWVYSGFEIDLKTDtdQVDLSSYYASSKYEILSAT 178
Cdd:cd19020  81 VlVNSSGHCQYLPPGIFKSSCYidvrwfPFDVQK-----CNLKFGSWTYGGWSLDLQMQ--EADISGYISNGEWDLVGVP 153

                       170       180
                ....*....|....*....|....*..
2Y7Y_B      179 QTRQVQHYSCCPEPYIDVNLVVKFRER 205
Cdd:cd19020 154 GKRNEKFYECCKEPYPDVTFTVTMRRR 180

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYS-STRPVQVLSPQIA 105
Cdd:cd19019   1 VTVHFEVAITQLVNVDEVNQIMETNLWLRHIWNDYKLRWDPREYDGIEFMRVPADKIWKPDIVLYNnAVGDFQVEGKTKA 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVTHDGSVMFIPAQRLSFMCdPTGVD--SEEGVTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQV 183
Cdd:cd19019  81 LLKYNGMITWTPPAIFKSSC-PMDITffPFDHQNCSLKFGSWTYDKAKIDLLIIGSKVDMNDFWENSEWEIVDASGYKHD 159

                       170
                ....*....|...
2Y7Y_B      184 QHYSCCPEPYIDV 196
Cdd:cd19019 160 IKYNCCEEIYTDI 172

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       29 VTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSSTR-PVQVLSPQIAVV 107
Cdd:cd19017   3 VRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWRPDIVLYNNADgDFAVTHLTKAHL 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      108 THDGSVMFIPAQRLSFMC--DPTGVDSEEGvTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSATQTRQVQH 185
Cdd:cd19017  83 FHDGRVQWTPPAIYKSSCsiDVTFFPFDQQ-NCTMKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRK 161

                       170
                ....*....|.
2Y7Y_B      186 YSCCPEPYIDV 196
Cdd:cd19017 162 YECCAEIYPDI 172

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSST-RPVQVLSPQIA 105
Cdd:cd19021   1 IVVELQLSLLQIIDVDEKNQVLITNAWLQMYWVDIYLSWDQYEYPGVQNLRFPSDQIWVPDILLYNSAdERFDATFHTNV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      106 VVTHDGSVMFIPAQRLSFMCD------PTGVDSeegvtCAVKFGSWVYSGFEIDLKtdTDQVDLSSYYASSKYEILSATQ 179
Cdd:cd19021  81 LVNYSGSCQYIPPGILKSTCYidvrwfPFDVQK-----CDLKFGSWTHSGWLIDLQ--MLEADISNYISNGEWDLVGVPG 153

                       170       180
                ....*....|....*....|....*.
2Y7Y_B      180 TRQVQHYSCCPEPYIDVNLVVKFRER 205
Cdd:cd19021 154 KRNELYYECCKEPYPDVTYTITMRRR 179

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B        6 RLKSDLFNRSPMYPGPTKD--DPLTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADI 83
Cdd:cd19032   4 RLVRDLFRGYNYLIRPVRNmsEPVEVNFGLALIQLINVDEKNQIMKTNVWLTMYWNDYQLKWDPADYGGIKVIRVPPDKV 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       84 WTPDITAYSSTR-PVQVLSPQIAVVTHDGSVMFIPAQRLSFMCDptgVDSE----EGVTCAVKFGSWVYSGFEI--DLKT 156
Cdd:cd19032  84 WKPDIVLFNNADgNYEVSYKSNVLIYSTGEVLWVPPAIYKSSCT---IDVEyfpfDQQECEMKFGSWTFNGDEVslDLYN 160

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*
2Y7Y_B      157 DTDQVDLSSYYASSKYEILSATQTRQVQHYSCCPEPYIDVNLVVK 201
Cdd:cd19032 161 NKKFVDLSDYWKSGTWDIIDVPGQLVNKDDAGPTETDIIFKIKIR 205

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       27 LTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAYSS---TRPVQVLSPq 103
Cdd:cd19027   1 VSIKLQLSLAQLISVNEREQIMTTNVWLNQEWTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNadgTYEVSVYTN- 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B      104 iAVVTHDGSVMFIPAQRLSFMCD------PtgVDSEegvTCAVKFGSWVYSGFEIDLKTDTDQVDLSSYYASSKYEILSA 177
Cdd:cd19027  80 -AIVQNNGSVAWLPPAIYKSACKievkhfP--FDQQ---NCTLKFRSWTYDHTEIDMVLKTPTASMDDFTPSGEWDIVAL 153

                       170       180
                ....*....|....*....|.
2Y7Y_B      178 TQTRQVqhyscCP-EP-YIDV 196
Cdd:cd19027 154 PGRRTV-----NPlDPtYVDV 169

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B        6 RLKSDLF-NRSP-MYPGPTKDDPLTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADI 83
Cdd:cd19024   3 QLLEKLFeNYNPkVRPARTVGDRVVVSVGLTLAQLISLNEKNEEMTTKVYLDLEWTDYRLSWDPAEYDGIDSLRITSDSV 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       84 WTPDIT-------AYSSTRPVQVLspqiavVTHDGSVMFIPAQRLSFMCdptgvdSEEgVT--------CAVKFGSWVYS 148
Cdd:cd19024  83 WLPDIVlmnnndgNFDVALDVNVL------VSSDGSVRWHPPAIYRSSC------SIE-VTyfpfdwqnCSMVFRSYTYD 149

                       170
                ....*....|.
2Y7Y_B      149 GFEIDLKTDTD 159
Cdd:cd19024 150 SSEVSLQHGLD 160

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B        6 RLKSDLFN----RSPMYPGPTKDDPLTVTLGFTLQDIVkvdsSTNEVDL-----VYYEQQrWKLNSLMWDPNEYGNITDF 76
Cdd:cd19028   2 RLINHLFIergyNKELRPVAHKDEVVNVALALTLSNLI----SLKEVDEtlttnVWVEHG-WYDHRLTWNASEYGNISIL 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       77 RTSAADIWTPDITAYSSTRPV-QVLSPQIAVVTHDGSVMFIPAQRLSFMCdPTGVD--SEEGVTCAVKFGSWVYSGFEID 153
Cdd:cd19028  77 RLPPEMVWLPEIVLENNNDGQfEVAYYCNVLVYSDGFVYWLPPAIFRSSC-PINVNyfPFDWQNCSLKFSSLNYNAKEIN 155

                       170
                ....*....|...
2Y7Y_B      154 LKTDTDQVDLSSY 166
Cdd:cd19028 156 LDLKTDTDDGKTY 168

extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit E (5HT3E); may include subunits C and D (5-HT3C,D); This subfamily contains extracellular domain of subunit E of serotonin 5-HT3 receptor (5-HT3ER), encoded by the HTR3E gene, and may also contain subunits C and D, all three encoding genes forming a cluster on chromosome 3. Data show that 5-HT3C, 5-HT3D, and 5-HT3E subunits are co-expressed with 5-HT3A in cell bodies of myenteric neurons, and that 5-HT3A and 5-HT3D are expressed in submucosal plexus of the human large intestine while HTR3E is restricted to the colon, intestine, and stomach. None of these subunits can form functional homopentamers, but, upon co-expression with the 5-HT3A subunit, they give rise to functional receptors that differ in maximal responses to 5-HT, and thus modulate 5-HT3 receptor's pharmacological profile. HTR3A and HTR3E polymorphisms have been shown to remarkably up-regulate the expression of 5-HT3 receptors, which have been proved to cause the gastric functional disorders including emesis, eating disorders and IBS-D.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       12 FNRSPMYPGPTKDDPLTVTLGFTLQDIVKVDSSTNEVDLVYYEQQRWKLNSLMWDPNEYGNITDFRTSAADIWTPDITAY 91
Cdd:cd19013  18 FDRKAFRPVMNLSTPTNVNISFTLYAILGVNEKAQLLTTFLWLRLVWDNEFLSWDPEECEGVTKISVPRENLWVPDIFIN 97

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
2Y7Y_B       92 SSTRPVQvlSPQI--AVVTHDGSVMFIPAQRLSFMCD------PTGVDSeegvtCAVKFGSWVYS 148
Cdd:cd19013  98 EFMDEDK--SPKVpyVYVSHTGRVRDDKPVRVVSSCNldiftfPFDIQN-----CTLTFGSYLHT 155

extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit A (5HT3A); This subfamily contains extracellular domain of subunit A of serotonin 5-HT3 receptor (5-HT3AR), encoded by the HTR3A gene. 5-HT3A subunit forms a homopentameric complex or a heterologous combination with other subunits (B-E). Heteromeric combination of A and B subunits provides the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. 5-HT3A receptors are located in the dorsal vagal complex of the brainstem and in the gastrointestinal (GI) tract, and form a channel circuit that controls gut motility, secretion, visceral perception, and the emesis reflex. These receptors are implicated in several GI and psychiatric disorder conditions including anxiety, depression, bipolar disorder, and irritable bowel syndrome (IBS). Several 5-HT3AR antagonists, such as the isoquinoline Palonosetron, are in clinical use to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. SNPs in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B        4 LMRLKSDLFNRSPMYPGPTKD--DPLTVTLGFTLQDIVKVDSStNEVDLVY-YEQQRWKLNSLMWDPNEYGNITDFRTSA 80
Cdd:cd19011   1 LLRLSDHLLEGYKKGVRPVRDwrKPTTVSIDVMVYAILNVDEK-NQVLTTYiWYRQYWTDEFLQWNPEDFDNVTQLSIPT 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2Y7Y_B       81 ADIWTPDITAyssTRPVQV-LSPQI--AVVTHDGSV------MFIPAQRLSFMCDPTGVDSeegvtCAVKFGSWVYS--G 149
Cdd:cd19011  80 DSIWVPDILI---NEFVDVgKSPEIpyVYVNHEGEVqnykpiQVVTACSLDIYNFPFDVQN-----CSLTFTSWLHTiqD 151

                       170       180
                ....*....|....*....|....*....
2Y7Y_B      150 FEIDLKTDTDQV--DLSSYYASSKYEILS 176
Cdd:cd19011 152 INISLWRSPEEVksDKSVFMNQGEWELLG 180