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 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 117168291 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 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 117168291 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19000  161 EIVKTTSGDYVVMTIYFDLSRR 182

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 117168291  260 TYIPCILTVVLSWVSFWIKKDATPARTTLGITTVLTMTTLSTIARKSLPRVSYVTAMDL-FVTVCFLFVFAALMEYATLN 338
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGkYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  339 YYSScRKPTiRKKKTSLLHPDSTRWIPDRISLQAP--------------SNYSLLDMRPPPPVMITLNNSMYWQEFEDTC 404
Cdd:pfam02932  81 NVHH-RSPS-THKMPPWVRKIFLEKLPRLLGMKRPpeappppaspgygsKAEEYILRKPRSELPFEKQSERHGLGRETTC 158

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 117168291  405 VYECLDGKDC---QSFFCCYEECKSG------SWRRGRIHIDVSE--------LDSYSRVFFPTSFLLFNLVYW 461
Cdd:pfam02932 159 SYGCSLGNGSsqpRELSPELKKAVEGvnfiakHLRSQDEYISVKEdwkyvamvIDRLSRWIFPIAFVLGTLGYF 232

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 117168291 255 YFTIQTYIPCILTVVLSWVSFWIKKDATPARTTLGITTVLTMTTLSTIARKSLPRVSYVTAMDLFVTVCFLFVFAALMEY 334
Cdd:cd19054    1 YFTIQTYIPCILTVVLSWVSFWINKDAVPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFAALMEY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 335 ATLNYYsscrkptirkkktsllhpdstrwipdrislqapsnyslldmrppppvmitlnnsmywqefedtcvyecldgkdc 414
Cdd:cd19054   81 GTLHYF-------------------------------------------------------------------------- 86

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 117168291 415 qsffccyeecksgswrrgrihiDVSELDSYSRVFFPTSFLLFNLVYW 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 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKSSVEVADQKSWRLYQFSFVGLRNTT 160

                        170       180
                 ....*....|....*....|..
gi 117168291 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 117168291  69 KPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPN 148
Cdd:cd19044    1 KPTVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 149 QLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRN 228
Cdd:cd19044   81 RMLRIWNDGRVLYTLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKRSSVEVGDTRSWRLYQFSFVGLRN 160

                        170       180
                 ....*....|....*....|....
gi 117168291 229 TTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19044  161 TTEVVKTTSGDYVVMSVYFDLSRR 184

extracellular domain of gamma-aminobutyric acid receptor subunit gamma-1 (GABAAR-G1 or GABRG1); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-1 (GABAAR-G1), a protein that is encoded by the GABRG1 gene in humans, clustered with the alpha2 gene GABRA2, which is associated with alcohol dependence. 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-1 subunit forms heteropentamers with other GABAAR subunits, likely expressed as combination of alpha1/2-beta-gamma1 subunits. A variant in GABRG1 shows the strongest statistical evidence of association of recovery from eating disorders. Studies show that upregulating or preserving GABAA gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in Alzheimer's disease.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19043    1 TVIETDVYVNSIGPVDPINMEYTIDIIFAQTWFDSRLKFNSTMKVLMLNSNMVGKIWIPDTFFRNSRKSDAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19043   81 LRIWSDGRVLYTLRLTINAECYLQLHNFPMDEHSCPLEFSSYGYPKNEIEYKWKKPSVEVADPKYWRLYQFAFVGLRNST 160

                        170       180
                 ....*....|....*....|..
gi 117168291 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19043  161 EISHTISGDYIIMTIFFDLSRR 182

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 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd18998    1 TEVKTDIYVTSFGPVSDVDMEYTIDVFFRQTWKDERLKFKGPMKILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKN---SVEAADQKSwRLYQFDFMGLR 227
Cdd:cd18998   81 LRIQDDGTLLYTMRLTIHAECPMHLEDFPMDAHSCPLKFGSYAYPKSEVVYTWTYGpkkSVEVAEDGS-RLNQYDLIGQT 159

                        170       180
                 ....*....|....*....|....*
gi 117168291 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 117168291  58 YDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSK 137
Cdd:cd19039    2 YDNRLRPGFGGPVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDERLKFGGPTEILRLNNLMVSKIWTPDTFFRNGK 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 138 TAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKN---SVEAADQK 214
Cdd:cd19039   82 KSISHNMTTPNKLFRIMQNGTILYTMRLTINAECPMRLVNFPMDGHACPLKFGSYAYPKSEIVYTWKKGplySVEVPEES 161

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 117168291 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 117168291  55 LREYDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFR 134
Cdd:cd19036    1 LDGYDNRLRPGLGDSVTEVKTDIYVTSFGPVSDTDMEYTIDVFFRQSWRDERLKFDGPMKILPLNNLLASKIWTPDTFFH 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 135 NSKTAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRW---RKNSVEAA 211
Cdd:cd19036   81 NGKKSVAHNMTTPNKLLRLVDNGTLLYTMRLTIHAECPMHLEDFPMDVHACPLKFGSYAYTKTEVVYSWtlgKNKSVEVA 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 117168291 212 DQKSwRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19036  161 PDGS-RLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLKRK 200

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-2 (GABAAR-A2 or GABRA2); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-2 (GABAAR-A2), a protein that is encoded by the GABRA2 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-2 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha2beta3gamma2. The alpha-2 (GABRA2) subunit is found primarily in the forebrain and hippocampus, and is more confined to areas of the brain compared to other alpha subunits. GABRA2 increases the risk of anxiety, making it a target for treating behavioral disorders including alcohol dependence, and drug use. GABRA2 is a binding site for benzodiazepines (psychoactive drugs known to reduce anxiety), causing chloride channels to open, leading to the hyper-polarization of the membrane. Other anxiolytic drugs such as Diazepam bind this subunit to induce inhibitory effects. GABRA2 is associated with reward behavior when it activates the insula, the part of the cerebral cortex responsible for emotions. GABA alpha2 and/or alpha3 receptor subtypes are also involved in GABAergic modulation of prolactin secretion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  52 NKLLREYDKKLRPDIGIKPTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDT 131
Cdd:cd19035    1 DRLLDGYDNRLRPGLGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQRWKDERLKFKGPMNILRLNNLMASKIWTPDT 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 132 IFRNSKTAEAHWITTPNQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKN---SV 208
Cdd:cd19035   81 FFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSCPLKFGSYAYTTSEVTYIWTYNasdSV 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 117168291 209 EAADQKSwRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19035  161 QVAPDGS-RLNQYDLLGQTIGKETIKSSTGEYTVMTAHFHLKRK 203

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 117168291  260 TYIPCILTVVLSWVSFWIKKDATPARTTLGITTVLTMTTLSTIARKSLPRVSYVTAMDL-FVTVCFLFVFAALMEYATLN 338
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGkYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  339 YYSScRKPTiRKKKTSLLHPDSTRWIPDRISLQAP--------------SNYSLLDMRPPPPVMITLNNSMYWQEFEDTC 404
Cdd:pfam02932  81 NVHH-RSPS-THKMPPWVRKIFLEKLPRLLGMKRPpeappppaspgygsKAEEYILRKPRSELPFEKQSERHGLGRETTC 158

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 117168291  405 VYECLDGKDC---QSFFCCYEECKSG------SWRRGRIHIDVSE--------LDSYSRVFFPTSFLLFNLVYW 461
Cdd:pfam02932 159 SYGCSLGNGSsqpRELSPELKKAVEGvnfiakHLRSQDEYISVKEdwkyvamvIDRLSRWIFPIAFVLGTLGYF 232

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 117168291  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN-STMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPN 148
Cdd:cd19007    1 PTTVETDILIRSMGPISELDMTYSMDCYFRQSWQDRRLAFNgPSIDTLSLSIKMLDRIWKPDTYFYNGKKSYLHTITTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 149 QLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNsVEAADQKSWRLYQFDFMG--L 226
Cdd:cd19007   81 KLVRLRQDGRILYSMRLTIKASCPMNLEKFPMDTQSCPLIIGSYGYTTKDVIYKWKDG-RDVVIAPDMTLSQFDLVGfpA 159

                        170       180
                 ....*....|....*....|....*.
gi 117168291 227 RNTTEIVTtsAGDYVVMTIYFELSRR 252
Cdd:cd19007  160 GNVTDIRR--GGNYSMLSVNFHLQRH 183

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 117168291  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFN--STMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTP 147
Cdd:cd18991    1 PTNVSVQIYINSIDSINEATMDYSVNIFLRQRWNDPRLNFTklSNIDYLELDPKMIDKIWVPDLFFPNEKKANFHDVTVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 148 NQLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSvEAADQKSWRLYQFDFMGLR 227
Cdd:cd18991   81 NKLLRIYPNGTVYYSMRLSLTLSCPMDLHKYPLDTQTCPIQIESFGYTTENLIFKWNDDK-PVQLNDGLELPQFELKGVS 159

                        170       180
                 ....*....|....*....|....*
gi 117168291 228 NTT-EIVTTSAGDYVVMTIYFELSR 251
Cdd:cd18991  160 TSDcTKTYTETGNFSCLEAKFHLQR 184

extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  71 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKI--LTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPN 148
Cdd:cd18987    1 TNVKVSIYIESISSIDEQTMDFTVDMYLRQRWTDPRLAYPDRNGTdpILLPSDKFDKIWLPDLYFRNEKSSSFHDVTTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 149 QLLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRN 228
Cdd:cd18987   81 VLVRIFPNGTVLYSQRLTLTLSCPMNLQKFPFDTQVCTLRLESYGYTTDQVVLHWDDDPPIVVNESSLLLPEFSLVKITT 160

                        170       180
                 ....*....|....*....|....*
gi 117168291 229 TTEIVT-TSAGDYVVMTIYFELSRR 252
Cdd:cd18987  161 SDCTGNySTTGNYSCLEATFKLKRE 185

gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such as RDL (resistant to dieldrin); This family contains extracellular domain of beta-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster resistant to dieldrin (RDL) 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. 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. Bombyx mori includes three RDL (RD1, RD2, RD3), one LCCH3, and one GRD subunits. Its RDL1 gene has RNA-editing sites, and the RDL1 and RDL3 genes possess alternative splicing, enhancing the diversity of its GABA-receptor gene family. The three RDL subunits may have arisen from two duplication events.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291  73 IDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKI--LTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 150
Cdd:cd19008    3 VGVTMYVLSISSVSEVDMDFTLDFYFRQFWTDPRLAFKKSPGVesLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSNEF 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 151 LRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNTT 230
Cdd:cd19008   83 LRIHHSGSITRSIRLTITASCPMNLQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGPNSVGISPEVELPQFKVLGHRQRA 162

                        170       180
                 ....*....|....*....|..
gi 117168291 231 EIVTTSAGDYVVMTIYFELSRR 252
Cdd:cd19008  163 REISLTTGNYSRLACEIQFVRS 184

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 117168291  70 PTVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQ 149
Cdd:cd19003    1 PVPVRISIYVSSIEQISEMNMDYTITMFFHQTWKDSRLAYYETTLNLTLDYRMHEKLWVPDCYFLNSKDAFVHDVTVENR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117168291 150 LLRIWNDGKILYTLRLTINAECQLQLHNFPMDAHACPLTFSSYGYPKEEMIYRWRKNSVEAADQKSWRLYQFDFMGLRNT 229
Cdd:cd19003   81 VFQLHPDGTVRYGIRLTTTAACSLDLHKFPMDKQACKLEVESYGYTVEDIILFWEDNGNAIHMTEELHIPQFTFLGRTIT 160

                        170       180
                 ....*....|....*....|..
gi 117168291 230 TEIVTTSAGDYVVMTIYFELSR 251
Cdd:cd19003  161 SKEVYFYTGSYIRLILKFQVQR 182