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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       27 VAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSS--HSPDQVSVPISSLWVPDLAAYNAISKPEVLT-PQLA 103
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAeyGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLFsPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      104 RVVSDGEVLYMPSIRQRFSCDVSGVDTESGATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQYSRFEILDVTQKKNSV 183
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYN-QSSKWELLSATQKREVK 159

                       170       180
                ....*....|....*....|.
3U8M_T      184 TYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd18995 160 TYSCCPEPYPDIEFVFTFKKR 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       27 VAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSS--HSPDQVSVPISSLWVPDLAAYNAISKPEVLT-PQLA 103
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAeyGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLFsPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      104 RVVSDGEVLYMPSIRQRFSCDVSGVDTESGATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQYSRFEILDVTQKKNSV 183
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYN-QSSKWELLSATQKREVK 159

                       170       180
                ....*....|....*....|.
3U8M_T      184 TYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd18995 160 TYSCCPEPYPDIEFVFTFKKR 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T          8 YNIRqtsrpdVIPTQRDRPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSPD--QVSVPISSLWVPD 85
Cdd:TIGR00860  42 YDAR------VRPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGvtLVRTPDDSIWVPD 115

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T         86 LAAYN-------AISKPEVLTpqlaRVVSDGEVLYMPSIRQRFSC---------DVSgvdtesgaTCRIKIGSWTHHSRE 149
Cdd:TIGR00860 116 IFFYNekdarfhGITMTNVLV----RIHPNGSVLYSPRITLTLACpmdlrnfpfDVQ--------NCSLKFESWGYTTND 183

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
3U8M_T        150 ISVDPTTEN---SDDSEYFSQySRFEILDVTQKKNSvTYSCCPEAYEDVEVSLNFRK 203
Cdd:TIGR00860 184 IKLEWKEQGavqVDDSLFISL-PEFELLGVYGTRYC-TSETNTGEYPCLTFSFVLRR 238

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       27 VAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSS--HSPDQVSVPISSLWVPDLAAYNAISKPEVLT-PQLA 103
Cdd:cd18995   1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAeyGNLKNLRLPSSKIWTPDIAVYNSIGAPSVLFsPQLV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      104 RVVSDGEVLYMPSIRQRFSCDVSGVDTESGATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQYSRFEILDVTQKKNSV 183
Cdd:cd18995  81 LVSSDGTVLWVPPIRIRFSCDLDNVDPEDGATCRLKIGSWTYSGREIDLNTGTDVDLDSYYN-QSSKWELLSATQKREVK 159

                       170       180
                ....*....|....*....|.
3U8M_T      184 TYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd18995 160 TYSCCPEPYPDIEFVFTFKKR 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       29 VSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSPD--QVSVPISSLWVPDLAAYNAISKPEVLT--PQLAR 104
Cdd:cd18989   3 VNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGitSIVVPSSEIWTPDIVLYNSVDSLDLLGdsNTLVR 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      105 VVSDGEVLYMPSIRQRFSCDVSG----VDTEsgaTCRIKIGSWTHHSREISVDPtTENSDDSEYFSQYSRFEILDVTQKK 180
Cdd:cd18989  83 VSSDGTVTWVPPGVLTTSCDIDVtyfpFDTQ---TCSLRFGSWSYTTDEINLTP-SSNGVDLEDYEENGEWELLSTSVSR 158

                       170       180
                ....*....|....*....|....
3U8M_T      181 NSVTYscCPEAYEDVEVSLNFRKK 204
Cdd:cd18989 159 EEDKY--CNETYSELTFTITLKRR 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T        5 DILYNIRQTSRPDVIPTQRdrPVAVSVSLKFINILEVNE----ITNEVdvvfWQQTTWSDRTLAWNSS--HSPDQVSVPI 78
Cdd:cd19031   8 DLLSNYNYNRRPRVTNDSD--TLTVKLGLKLSQLIDVDEknqiMTTNV----WLEQEWYDYKLVWDPAeyGGVEMLYVPS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       79 SSLWVPDLAAYN-AISKPEVLTPQLARVVSDGEVLYMPSIRQRFSCDVsgvDTE----SGATCRIKIGSWTHHSREISVD 153
Cdd:cd19031  82 EDIWLPDIVLYNnADGNYEVTLMTKATLHYNGTVRWEPPAIYKSSCEI---DVEyfpfDEQTCFMKFGSWTYDGFEVDLR 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|.
3U8M_T      154 PTTENSDDSEYFSQYS----------RFEILDVTQKKNSVTYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd19031 159 HVDQKYGSEDEVIDVGidlsefypsvEWDLLEVPARRNEKYYPCCDEPYPDITFNITLRRK 219

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       14 SRPdvIPTQRDrPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSPDQVS--VPISSLWVPDLAAYNA 91
Cdd:cd19015  16 SRP--VPNTSD-VVIVKFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKLRWNPTDFDNVTSirVPSEMIWIPDIVLYNN 92

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       92 ISKPEVLTPQL-ARVVSDGEVLYMPSIRQRFSC--DVSGVDTESgATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQY 168
Cdd:cd19015  93 ADGEFAVTHMTkAHLFSTGKVKWVPPAIYKSSCsiDVTFFPFDQ-QNCKMKFGSWTYDKAKIDLEQMEQTVDLKDYW-ES 170

                       170       180       190
                ....*....|....*....|....*....|....*
3U8M_T      169 SRFEILDVTQKKNSVTYSCCPEAYEDVEVSLNFRK 203
Cdd:cd19015 171 GEWAIVNATGTYNSKKYDCCTEIYPDITYYFVIRR 205

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSP--DQVSVPISSLWVPDLAAYNAISKPEVLTPQLA 103
Cdd:cd19020   1 PLTVYFSLSLMQIMDVDEKNQVLTTNIWLQMYWTDHYLQWNASEYPgvKNVRFPDGQIWKPDILLYNSADERFDATFHTN 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      104 RVV-SDGEVLYMPSIRQRFSC--DVSGVDTESgATCRIKIGSWTHHSreISVDPTTENSDDSEYFSQySRFEILDVTQKK 180
Cdd:cd19020  81 VLVnSSGHCQYLPPGIFKSSCyiDVRWFPFDV-QKCNLKFGSWTYGG--WSLDLQMQEADISGYISN-GEWDLVGVPGKR 156

                       170       180
                ....*....|....*....|....
3U8M_T      181 NSVTYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd19020 157 NEKFYECCKEPYPDVTFTVTMRRR 180

extracellular domain of neuronal acetylcholine receptor subunit alpha 9 (CHRNA9); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 9 (alpha9), encoded by the CHRNA9 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Mammalian alpha9 subunits can form functional homomeric alpha9 receptors as well as the heteromeric alpha9alpha10 receptors, the latter being atypical since the heteromeric alpha9alpha10 receptor is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms. CHRNA9 polymorphisms are associated with non-small cell lung cancer, and effect of a particular SNP (rs73229797) and passive smoking exposure on risk of breast malignancy has been observed.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       24 DRPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSP--DQVSVPISSLWVPDLAAYNAiSKPEVLTPQ 101
Cdd:cd19022  23 DKVLNVTLQITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDglDSIRIPSNLVWRPDIVLYNK-ADDEFSEPV 101

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      102 LARVV--SDGEVLY-MPSIRQRfSC--DVSGVDTESgATCRIKIGSWTHHSREISVDPTTENSDDSEyFSQYSRFEILDV 176
Cdd:cd19022 102 NTNVVlrYDGKITWdAPAITKS-SCvvDVSYFPFDN-QQCNLTFGSWTYNGNQVDIINALDSGDLSD-FVEDVEWEVHGM 178

                       170       180
                ....*....|....*....|....*...
3U8M_T      177 TQKKNSVTYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd19022 179 PAVKNVITYGCCSEPYPDVTFTLILKRR 206

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSH--SPDQVSVPISSLWVPDLAAYN-AISKPEVLTPQL 102
Cdd:cd19016  25 PVIIQFEVSMSQLVKVDEVNQIMETNLWLKHIWNDYKLKWNPSDygGAEFMRVPAEKIWKPDIVLYNnAVGDFQVDDKTK 104

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      103 ARVVSDGEVLYMPSIRQRFSC--DVSGVDTESgATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQYSRFEILDVTQKK 180
Cdd:cd19016 105 ALLKYTGEVTWIPPAIFKSSCkiDVTYFPFDY-QNCTMKFGSWSYDKAKIDLVLIGSSMNLKDYW-ESGEWAIIKAPGYK 182

                       170       180
                ....*....|....*....|...
3U8M_T      181 NSVTYSCCPEAYEDVEVSLNFRK 203
Cdd:cd19016 183 HDIKYNCCEEIYPDITYSLYIRR 205

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       27 VAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSP--DQVSVPISSLWVPDLAAYNAISKPEVLTPQLAR 104
Cdd:cd19021   1 IVVELQLSLLQIIDVDEKNQVLITNAWLQMYWVDIYLSWDQYEYPgvQNLRFPSDQIWVPDILLYNSADERFDATFHTNV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      105 VVS-DGEVLYMPSIRQRFSC--DVSGVDTESgATCRIKIGSWTHHSREIsvDPTTENSDDSEYFSQySRFEILDVTQKKN 181
Cdd:cd19021  81 LVNySGSCQYIPPGILKSTCyiDVRWFPFDV-QKCDLKFGSWTHSGWLI--DLQMLEADISNYISN-GEWDLVGVPGKRN 156

                       170       180
                ....*....|....*....|...
3U8M_T      182 SVTYSCCPEAYEDVEVSLNFRKK 204
Cdd:cd19021 157 ELYYECCKEPYPDVTYTITMRRR 179

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T        4 ADILYNIRQTSRPdvIPTQRDrPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNsshsPD------QVSVP 77
Cdd:cd19014   8 ADLFKNYNKVVRP--VEHHKD-FVVVTVGLQLIQLINVDEVNQIVTTNVRLKQQWIDVNLKWN----PDdyggikKIRIP 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       78 ISSLWVPDLAAYNAiSKPEVLTPQLARVVSD--GEVLYMPSIRQRFSCDVS----GVDTESgatCRIKIGSWTHHSREIS 151
Cdd:cd19014  81 SSDIWRPDLVLYNN-ADGDFAIVKETKVLLEytGKITWTPPAIFKSYCEIIvthfPFDQQN---CSMKLGTWTYDGTLVV 156

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*
3U8M_T      152 VDPTTENSDDSEyFSQYSRFEILDVTQKKNSVTYSCCPEA-YEDV 195
Cdd:cd19014 157 INPESDRPDLSN-FMESGEWVMKDYRGWKHWVYYTCCPDTpYLDI 200

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       27 VAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSPDQVSVPISS--LWVPDLAAYN-AISKPEVLTPQLA 103
Cdd:cd19017   1 VLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSelIWRPDIVLYNnADGDFAVTHLTKA 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      104 RVVSDGEVLYMPSIRQRFSC--DVSGVDTESgATCRIKIGSWTHHSREISVDPTTENSDDSEYFsQYSRFEILDVTQKKN 181
Cdd:cd19017  81 HLFHDGRVQWTPPAIYKSSCsiDVTFFPFDQ-QNCTMKFGSWTYDKAKIDLVSMHSRVDQLDFW-ESGEWVIVDAVGTYN 158

                       170       180
                ....*....|....*....|..
3U8M_T      182 SVTYSCCPEAYEDVEVSLNFRK 203
Cdd:cd19017 159 TRKYECCAEIYPDITYAFIIRR 180

extracellular domain of serotonin 5-HT3 receptor; This family contains extracellular domain of serotonin 5-HT3 receptor which belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs). This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       25 RPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSH--SPDQVSVPISSLWVPDLAAYNAISKPEVLTPQL 102
Cdd:cd18996  31 PPTTVYLDLTLYAILDVDEKLQTLTTYIWLEMVWFNEFLSWNPEQfcGISKVSVPEDTLWKPDILIYEMTDKDKSPKIPY 110

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T      103 ARVVSDGEVLYMPSIRQRFSCDVS----GVDTEsgaTCRIKIGSWTHHSREISVDPTTENSD----DSEYFSQYSRFEIL 174
Cdd:cd18996 111 VYVSNNGTVRNYKPLQVVSTCSLDiykfPFDTQ---NCNLTFSSFLHTVNDIILNPGSNSEEitseSKEIFQTQGEWELL 187

                ...
3U8M_T      175 DVT 177
Cdd:cd18996 188 NIK 190

extracellular domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family contains extracellular domain (ECD) of bacterial pentameric ligand-gated ion channels (pLGICs), including ones from Gloebacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC). These prokaryotic homologs of Cys-loop receptors have been useful in understanding their eukaryotic counterparts. The largely beta-sheet ECD in this family is similar to other pLGICs, but lacks the cysteine loop and an intracellular domain. While most pLGICs undergo desensitization on prolonged exposure to the agonist, GLIC is activated by protons, but does not desensitize, even at proton concentrations eliciting maximal electrophysiological response (pH 4.5). Studies show that GLIC activation is inhibited by most general anaesthetics at clinical concentrations, including xenon which has been used in clinical practice as a potent gaseous anesthetic for decades. Xenon binding sites have been identified in three distinct regions of the TMD: in a large intra-subunit cavity, in the pore, and at the interface between adjacent subunits.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAwnssHSPDQVSV--------PISSLWVPDLAAYNAISKPEV 97
Cdd:cd18988   1 PTEVSVGIYLIDIYGIDEVNETFEADGYLRLRWQDPRLA----FDPAAGKEyrlgeaekQLDEIWNPQIEFINQRGLRDT 76

                        90       100
                ....*....|....*....|....*
3U8M_T       98 LTPQLaRVVSDGEVLYmpsiRQRFS 122
Cdd:cd18988  77 LNRRL-RVFPDGTVTY----RQRFT 96

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       23 RDRPVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSS--HSPDQVSVPISSLWVPDL-------AAYNAIS 93
Cdd:cd19028  23 KDEVVNVALALTLSNLISLKEVDETLTTNVWVEHGWYDHRLTWNASeyGNISILRLPPEMVWLPEIvlennndGQFEVAY 102

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       94 KPEVLtpqlarVVSDGEVLYMPSIRQRFSCDVSGV----DTESgatCRIKIGSWTHHSREISVDPTTENSDDSEY----- 164
Cdd:cd19028 103 YCNVL------VYSDGFVYWLPPAIFRSSCPINVNyfpfDWQN---CSLKFSSLNYNAKEINLDLKTDTDDGKTYpvewi 173

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*...
3U8M_T      165 ------FSQYSRFEILDVTQKKNsVTYSCCPEA--YEDVEVSLNFRKK 204
Cdd:cd19028 174 iidpegFTENGEWEIVHKPAKKN-IDPSKPPEStkYQDITFYLIIKRK 220

extracellular domain of gamma-aminobutyric acid receptor subunit pi (GABRP); This family contains extracellular domain of pi subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABRP is expressed mainly in non-neuronal tissues such as the mammary gland, prostate gland, lung, thymus, and uterus. It is also highly expressed in certain types of cancer such as basal-like breast cancer and pancreatic ductal adenocarcinoma. GABRP is involved in inhibitory synaptic transmission in the central nervous system. Its assembly with other GABAAR subunits alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Studies suggest that polymorphisms in the GABRP gene may be associated with the susceptibility to systematic lupus erythematosus (SLE).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNSSHSPDQVSVPISSLWVPDlaAYNAISKPEVLTP----- 100
Cdd:cd19004   1 PVTVGMSLDIASIDTISEINMDYTATIFLRQRWTDERLCFEGNKSLSLDGRLVELLWVPD--TFIVDSKKSFLHDitven 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
3U8M_T      101 QLARVVSDGEVLYMPSIRQRFSCDVS----GVDTEsgaTCRIKIGSWTHHSREI 150
Cdd:cd19004  79 RLIRIFPNGTVLYALRITTTVACSMDltkyPMDKQ---TCTLQLESWGYNINDV 129

extracellular domain of gamma-aminobutyric acid receptor subunit delta; This family contains extracellular domain of delta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. Receptors containing the delta subunit (GABRD) are expressed exclusively extra-synaptically (in the cortex, hippocampus, thalamus, striatum, and cerebellum) and mediate tonic inhibition. Studies suggest that delta subunits form heteropentamers in similar stoichiometry and arrangement as alpha/beta/gamma receptors, with the delta subunit replacing the gamma subunit (2alpha:2beta:1delta), although other stoichiometries have also been detected. The delta subunit is flexible in its positioning in the pentameric complex, producing receptors with diverse pharmacological properties. Mutations in GABRD have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. GABRD gene may also be associated with childhood-onset mood disorders.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDVVFWQQTTWSDRTLAWNssHSPDQVSVP---ISSLWVPDLAAYNAISK---PEVLT 99
Cdd:cd19001   1 PVNVALAIEVASIDHISEVNMEYTMTVFLHQSWRDERLSYN--HTNETLGLDsrfVDKLWLPDTFIVNAKSAwfhDVTVE 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
3U8M_T      100 PQLARVVSDGEVLYMPSIRQRFSCDVS----GVDTESgatCRIKIGSWTHHSREI 150
Cdd:cd19001  79 NKLIRLQPDGVILYSSRITSTVACDMDltkyPMDEQE---CMLDLESYGYSSEDI 130

extracellular domain of glycine receptor (GlyR); This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) of the amino acid neurotransmitter glycine. GlyR has four known isoforms of the alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands and a single beta-subunit (encoded by GLRB), all of which have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). Functional chloride-permeable GlyR ion channels are formed by 5 alpha subunit homopentamers or by alpha and beta subunit heteropentamers, which form complexes with either a 2alpha-3beta or 3alpha-2beta stoichiometry. The receptor can be activated by glycine as well as beta-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine is also a competitive antagonist of GlyR. In human, glycine receptor alpha1 and beta subunits are the major targets of mutations that cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions, leading to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli. Mutations in GlyR alpha2 are known to cause cortical neuronal migration/autism spectrum disorder and in GlyR alpha3 to cause inflammatory pain sensitization/rhythmic breathing.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3U8M_T       26 PVAVSVSLKFINILEVNEITNEVDV-VFWQQTtWSDRTLAWNSSHSPDQVSVP---ISSLWVPDL-------AAYNaisk 94
Cdd:cd18991   1 PTNVSVQIYINSIDSINEATMDYSVnIFLRQR-WNDPRLNFTKLSNIDYLELDpkmIDKIWVPDLffpnekkANFH---- 75

                        90       100       110
                ....*....|....*....|....*....|..
3U8M_T       95 pEVLTP-QLARVVSDGEVLYmpSIR--QRFSC 123
Cdd:cd18991  76 -DVTVPnKLLRIYPNGTVYY--SMRlsLTLSC 104

extracellular domain of zinc-activated ligand-gated ion channel; This family is the extracellular domain of zinc-activated ligand-gated ion channel (ZAC), a cationic ion channel belonging to the superfamily of Cys-loop receptors, which consists of pentameric ligand-gated ion channels. ZAC displays low sequence similarity to other members in the superfamily, with closest matches to the human serotonin 5-HT3 receptor (5-HT3R) subunits 5-HT3A and 5-HT3B, and nAChR alpha7 subunits that exhibit approximately 15% amino acid sequence identity to ZAC. Expression of ZAC has been detected in human fetal whole brain, spinal cord, pancreas, placenta, prostate, thyroid, trachea, and stomach, as well as in adult hippocampus, striatum, amygdala, and thalamus. 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 is as yet unknown.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
3U8M_T       55 QTTWSDRTLAWNSSHSPDQ-VSVPISSLWVPDLAAYNAIS---KPEvlTPQlARVVSDGEVLYMPSIRQRFSCD 124
Cdd:cd18994  29 NLSWLDPRLAWNENISPMSaVTLPWDSLWTPGLTIQEALWvtwRPQ--SPD-ARVTRDGHVELYLALTTETNCD 99