extracellular domain of gamma-aminobutyric acid receptor subunit gamma; This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 110347416 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19000  161 EIVKTTSGDYVVMTIYFDLSRR 182

extracellular domain of gamma-aminobutyric acid receptor subunit gamma; This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 110347416 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19000  161 EIVKTTSGDYVVMTIYFDLSRR 182

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 110347416   48 TLILNKLLREYDKKLRPD-IGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN----STMKILTLNSNM 122
Cdd:pfam02931   2 ERLLDDLLSGYDKLVRPVaNGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNpedyGGITSLRLPSDK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  123 vglIWIPDTIFRNSKtAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYR 202
Cdd:pfam02931  82 ---IWKPDIVLYNKA-DGIHEVTTPNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLR 157

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 110347416  203 WRKNSVEAADQKsWRLYQFDFMGLRNTTE----IVTTSAGDYVVM----TIYFELSRRM 253
Cdd:pfam02931 158 WDDDPPVVELEE-IDLSDFWLNGEWDIVDvpakRREYPYGCYSELtgdvTFYFTLRRKP 215

transmembrane domain of gamma subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the gamma subunit of type-A beta-aminobutyric acid receptor (GABAAR), which includes gamma1-gamma3 in vertebrates. 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. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. Studies show upregulating or preserving GABAA gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in Alzheimer's disease. Pathogenic missense and truncating variants in GABRG2 have been associated with spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. Polymorphisms in GABG3 show consistent evidence of alcohol dependence.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 255 YFTIQTYIPCILTVVLSWVSFWIKKDATPARTALGITTVLTMTTLSTIARKSLPRVSYVTAMDLFVTVCFLFVFAALMEY 334
Cdd:cd19054    1 YFTIQTYIPCILTVVLSWVSFWINKDAVPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFAALMEY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 335 ATLNYYsscrkptttkkttsllhpdssrwiperislqapsnyslldmrppptamitlnnsvywqefedtcvyecldgkdc 414
Cdd:cd19054   81 GTLHYF-------------------------------------------------------------------------- 86

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 110347416 415 qsffccyeecksgswrkgrihiDILELDSYSRVFFPTSFLLFNLVYW 461
Cdd:cd19054   87 ----------------------RIAKIDSYSRIFFPTAFLLFNLVYW 111

extracellular domain of gamma-aminobutyric acid receptor subunit gamma; This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 110347416 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19000  161 EIVKTTSGDYVVMTIYFDLSRR 182

extracellular domain of gamma-aminobutyric acid receptor subunit gamma-2 (GABAAR-G2 or GABRG2); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-2 (GABAAR-G2), a protein that is encoded by the GABRG2 gene in humans. 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. The gamma-2 subunit forms heteropentamers with other GABAAR subunits, most prevalently expressed as alpha1-beta2-gamma2. The gamma2 subunit also coassembles with other alpha and beta variants in the brain, but these receptors are found in considerably less abundance and are restricted in their regional, e.g. the alpha2-beta3-gamma2 and alpha3-beta3-gamma2 subtypes are highly enriched in hippocampal pyramidal neurons and cholinergic neurons of the basal forebrain, respectively. Pathogenic missense and truncating variants in this gene have been associated with spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures, while a recurrent GABRG2 missense variant is associated with early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features, and vision/ocular issues.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  69 KPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPN 148
Cdd:cd19044    1 KPTVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 149 QLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRN 228
Cdd:cd19044   81 RMLRIWNDGRVLYTLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKRSSVEVGDTRSWRLYQFSFVGLRN 160

                        170       180
                 ....*....|....*....|....
gi 110347416 229 TTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19044  161 TTEVVKTTSGDYVVMSVYFDLSRR 184

Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416   50 ILNKLLREYDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN-STMKILTLNSNMVGLIWI 128
Cdd:TIGR00860  34 LLDELLKNYDARVRPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNpEEYPGVTLVRTPDDSIWV 113

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  129 PDTIFRNSKTAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRW-RKNS 207
Cdd:TIGR00860 114 PDIFFYNEKDARFHGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKLEWkEQGA 193

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  208 VEAADQKSWRLYQFDFMGLRNT-TEIVTTSAGDYVVMTIYFELSRRMGYFTIQTYIPCILTVVLSWVSFWIKKDATPART 286
Cdd:TIGR00860 194 VQVDDSLFISLPEFELLGVYGTrYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADASGARV 273

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  287 ALGITTVLTMTTLSTIARKSLPRVSYVTAMDLFVTVCFLFVFAALMEYATLNYYSscRKPTTTKKTTSLLHpdssrWIPE 366
Cdd:TIGR00860 274 SLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFLALLETAFVNYVH--HKDPAQGKRHLLLE-----RCAW 346

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  367 RISLQAPSNysllDMRPPPTAMITL-----NNSVYWQEFEDTCVYECLDGKDCQSFFCCYEECKSGSWRKGR-------- 433
Cdd:TIGR00860 347 RLCKQEPGE----DYRRPALDHASLssvemRAKDGGRGLESPTERQRLLHSPPPAEGDLDLAGILEEVRIAHrfrkrdes 422

                         410       420       430
                  ....*....|....*....|....*....|....*..
gi 110347416  434 --IHIDILE----LDSYSRVFFPTSFLLFNLVYWVGY 464
Cdd:TIGR00860 423 eeVVRDWKFrakvIDKLSRMAFPLAFLLFNIGYWMSY 459

extracellular domain of gamma-aminobutyric acid receptor subunit alpha; This family contains extracellular domain (ECD) of type-A gamma-aminobutyric acid receptor (GABAAR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. This family includes 19 isoforms in human; six alpha, 3 beta, 3 gamma, one of delta, epsilon, pi, and theta, known to form heteromeric GABAARs, and 3 rho subunits that only form homomeric channels (also known as GABAA rho or GABAC receptor) or pseudoheteromeric if consisting of different rho subunits. GABAAR is assembled from a variety of different subunit subtypes which determines their pharmacology and physiology; the most abundant being 2alpha2beta1gamma stoichiometry. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to its 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. Benzodiazepine and barbiturates each bind to their own distinct sites on the ECD. The channels have to contain the gamma subunit and alpha subunits in order to respond to benzodiazepines. All these major classes of drugs favor channel-opening. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABRA1, GABRA3, GABRB3, GABRG2, and GABRD, encoding the alpha1-, alpha3-, beta2-, gamma3-, and delta-subunits have been directly associated with epilepsy. Specific combinations of alpha, beta, and gamma subunits exhibit ethanol sensitivity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd18998    1 TEVKTDIYVTSFGPVSDVDMEYTIDVFFRQTWKDERLKFKGPMKILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKN---SVEAADQKSwRLYQFDFMGLR 227
Cdd:cd18998   81 LRIQDDGTLLYTMRLTIHAECPMHLEDFPMDAHSCPLKFGSYAYPKSEVVYTWTYGpkkSVEVAEDGS-RLNQYDLIGQT 159

                        170       180
                 ....*....|....*....|....*
gi 110347416 228 NTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd18998  160 VGSETIKSSTGEYVVMTVHFHLKRK 184

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6 or GABRA6); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6), a protein that is encoded by the GABRA6 gene in humans. 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. The alpha-6 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha6-beta-gamma2 found extrasynaptically, alpha6-beta2/3-delta in the cerebellar granule cells and likely also forms alpha1-alpha6-beta-gamma/alpha1-alpha6-beta-delta. A GABRA6 mutation from Arg to Trp, has been identified as a susceptibility gene that may contribute to the pathogenesis of childhood absence epilepsy and cause neuronal disinhibition and increase in seizures via a reduction of alphabetagamma and alphabetadelta receptor function and expression. Polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress. Alpha6-containing receptors lack high sensitivity to diazepam.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  58 YDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSK 137
Cdd:cd19039    2 YDNRLRPGFGGPVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDERLKFGGPTEILRLNNLMVSKIWTPDTFFRNGK 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 138 TAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKN---SVEAADQK 214
Cdd:cd19039   82 KSISHNMTTPNKLFRIMQNGTILYTMRLTINAECPMRLVNFPMDGHACPLKFGSYAYPKSEIVYTWKKGplySVEVPEES 161

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 110347416 215 SwRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19039  162 S-SLLQYDLIGQTVSSETLKSNTGEYVVMTVYFHLQRK 198

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3 or GABRA3); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3), a protein that is encoded by the GABRA3 gene in humans. 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. The alpha-3 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha3betagamma2, typically found post-synaptically. Rare loss-of-function variants in GABRA3 have been shown to increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay, and dysmorphic features. GABRA3, normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression being inversely correlated with breast cancer survival. It activates the AKT pathway to promote breast cancer cell migration, invasion, and metastasis. GABRA3 promotes lymphatic metastasis in lung adenocarcinoma by mediating upregulation of matrix metalloproteinases, MMP-2 and MMP-9, through activation of the JNK/AP-1 signaling pathway. GABRA3 is overexpressed in human hepatocellular carcinoma growth and, with GABA, promotes the proliferation of cancer cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  55 LREYDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFR 134
Cdd:cd19036    1 LDGYDNRLRPGLGDSVTEVKTDIYVTSFGPVSDTDMEYTIDVFFRQSWRDERLKFDGPMKILPLNNLLASKIWTPDTFFH 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 135 NSKTAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRW---RKNSVEAA 211
Cdd:cd19036   81 NGKKSVAHNMTTPNKLLRLVDNGTLLYTMRLTIHAECPMHLEDFPMDVHACPLKFGSYAYTKTEVVYSWtlgKNKSVEVA 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 110347416 212 DQKSwRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19036  161 PDGS-RLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLKRK 200

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4 or GABRA4); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4), a protein that is encoded by the GABRA4 gene in humans, with biased expression in the brain and heart. 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. The alpha-4 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha2alpha4beta1gamma1, all four subunits existing on the same gene cluster. Alpha-4 is involved in the etiology of autism and eventually increases autism risk through interaction with the beta-1 (GABRB1) subunit. Polymorphism in GABRA4 may trigger migraine by ethanol, while another is associated to faster reaction times and with lower ethanol effects. A rare variant in GABRA4 may have modest physiological effect in autism spectrum disorder etiology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  58 YDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSK 137
Cdd:cd19037    3 YDNRLRPGFGGPVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWVDKRLKYDGPIEILRLNNLMVTKVWTPDTFFRNGK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 138 TAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRK---NSVEAADQK 214
Cdd:cd19037   83 KSVAHNMTAPNKLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKgpeKSVEVPPES 162

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 110347416 215 SwRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19037  163 S-SLVQYDLIGQTVSSETIKSITGEYIVMTVYFHLRRK 199

gamma-aminobutyric acid receptor subunit alpha-like extracellular domain in protostomia, such as GRD (GABA/glycine-like receptor of Drosophila); This family contains extracellular domain of alpha-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster GABA/ glycine-like receptor of Drosophila (GRD) subunits. Drosophila melanogaster expresses three GABA-receptor subunit orthologs: (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila; LCCH3, ligand-gated chloride channel homolog 3), and may possibly form homo- and/or heteropentameric associations. LCCH3 has been shown to combine with subunit GRD to form cation-selective GABA-gated ion channels when co-expressed in Xenopus laevis oocytes. GABAARs are known to be the molecular targets of a class of insecticides. The resulting pentameric receptors in this family have been shown to be activated by insect GABA-receptor agonists muscimol and CACA, and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline. GABAARs are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN-STMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPN 148
Cdd:cd19007    1 PTTVETDILIRSMGPISELDMTYSMDCYFRQSWQDRRLAFNgPSIDTLSLSIKMLDRIWKPDTYFYNGKKSYLHTITTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 149 QLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNsVEAADQKSWRLYQFDFMG--L 226
Cdd:cd19007   81 KLVRLRQDGRILYSMRLTIKASCPMNLEKFPMDTQSCPLIIGSYGYTTKDVIYKWKDG-RDVVIAPDMTLSQFDLVGfpA 159

                        170       180
                 ....*....|....*....|....*.
gi 110347416 227 RNTTEIVTtsAGDYVVMTIYFELSRR 252
Cdd:cd19007  160 GNVTDIRR--GGNYSMLSVNFHLQRH 183

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 110347416  260 TYIPCILTVVLSWVSFWIKKDATPARTALGITTVLTMTTLSTIARKSLPRVSYVTAMDL-FVTVCFLFVFAALMEYATLN 338
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGkYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  339 YYSScRKPTTtkkttsllHPDSSR-------WIPERISLQAP--------------SNYSLLDMRPPPTAMITLNNSVYW 397
Cdd:pfam02932  81 NVHH-RSPST--------HKMPPWvrkifleKLPRLLGMKRPpeappppaspgygsKAEEYILRKPRSELPFEKQSERHG 151

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  398 QEFEDTCVYECLDGKDC---QSFFCCYEECKSG------SWRKGRIHIDILE--------LDSYSRVFFPTSFLLFNLVY 460
Cdd:pfam02932 152 LGRETTCSYGCSLGNGSsqpRELSPELKKAVEGvnfiakHLRSQDEYISVKEdwkyvamvIDRLSRWIFPIAFVLGTLGY 231

                  .
gi 110347416  461 W 461
Cdd:pfam02932 232 F 232

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN--STMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTP 147
Cdd:cd18991    1 PTNVSVQIYINSIDSINEATMDYSVNIFLRQRWNDPRLNFTklSNIDYLELDPKMIDKIWVPDLFFPNEKKANFHDVTVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 148 NQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSvEAADQKSWRLYQFDFMGLR 227
Cdd:cd18991   81 NKLLRIYPNGTVYYSMRLSLTLSCPMDLHKYPLDTQTCPIQIESFGYTTENLIFKWNDDK-PVQLNDGLELPQFELKGVS 159

                        170       180
                 ....*....|....*....|....*
gi 110347416 228 NTT-EIVTTSAGDYVVMTIYFELSR 251
Cdd:cd18991  160 TSDcTKTYTETGNFSCLEAKFHLQR 184

transmembrane domain of anionic Cys-loop neurotransmitter-gated ion channels, includes GABAAR, GlyR and GluCl; This family contains transmembrane domain of type-A gamma-aminobutyric acid receptor (GABAAR) as well as glycine receptor (GlyR) subunits. Thus far, there are 18 vertebrate receptor subunits categorized in 7 families: alpha1-6, beta1-4, gamma1-4, delta, epsilon, theta, rho, and pi. 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. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. GlyR, with a similar structure as GABAAR, is concentrated in the brain stem and spinal cord in the CNS and can be activated by glycine, beta-alanine, or taurine. It is selectively blocked by the high-affinity competitive antagonist strychnine, which causes death by asphyxiation. An autosomal dominant R271Q mutation in GLRA1 causes hyperekplexia (Startle disease or Stiff Baby Syndrome) by decreasing glycine sensitivity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 255 YFTIQTYIPCILTVVLSWVSFWIKKDATPARTALGITTVLTMTTLSTIARKSLPRVSYVTAMDLFVTVCFLFVFAALMEY 334
Cdd:cd19049    1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                         90
                 ....*....|
gi 110347416 335 ATLNYYSSCR 344
Cdd:cd19049   81 AVVNYLKASK 90

glutamate-gated chloride channel (GluCl) extracellular domain; This subfamily contains extracellular domain of glutamate-gated chloride channel (GluCl) found only in protostomia, but are closely related to mammalian glycine receptors. They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Comparison of the GluCl gene families between organisms shows that insect gene family is relatively simple, while that found in nematodes tends to be larger and more diverse. Glutamate is an inhibitory neurotransmitter that shapes the responses of projection neurons to olfactory stimuli in the Drosophila. GluCls are targeted by the macrocyclic lactone family of anthelmintics and pesticides in arthropods and nematodes, thus making the GluCls of considerable medical and economic importance. In Drosophila melanogaster, GluCl mediates sensitivity to the antiparasitic agents ivermectin and nodulisporic acid, suggesting that their drug target is the same throughout the Ecdysozoa.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNST---MKILTLNSnmVGLIWIPDTIFRNSKTAEAHWITT 146
Cdd:cd18993    1 PVIVKVNIYVRSISKIDDVKMEYSVQLTFRQEWYDPRLRYDDTggkPEYLTLTD--DSKIWKPDTFFQNEKEGHFHNIDK 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 147 PNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNS-VEAADQKSwrLYQFDFMG 225
Cdd:cd18993   79 PNVYLRIYPDGKVLYSVRISLTLSCPMDLQYYPFDKQTCSIDLASYGYTTDDIVYLWKEEDpVQLPKGLS--LPNFTLTN 156

                        170       180
                 ....*....|....*....|....*..
gi 110347416 226 LRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd18993  157 FKTGYCTSKTNTGEYSCLRVDFILRRE 183

extracellular domain of gamma-aminobutyric acid receptor subunit theta (GABRQ); This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR), and encoded by the GABRQ gene, which is mapped to chromosome Xq28 in a cluster of genes that also that encode the alpha 3 and epsilon subunits. 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. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. 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. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAAR theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQ 149
Cdd:cd19003    1 PVPVRISIYVSSIEQISEMNMDYTITMFFHQTWKDSRLAYYETTLNLTLDYRMHEKLWVPDCYFLNSKDAFVHDVTVENR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 110347416 150 LLRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNT 229
Cdd:cd19003   81 VFQLHPDGTVRYGIRLTTTAACSLDLHKFPMDKQACKLEVESYGYTVEDIILFWEDNGNAIHMTEELHIPQFTFLGRTIT 160