transmembrane domain of Cys-loop neurotransmitter-gated ion channels; This superfamily contains the transmembrane domain of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR), and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system where the sign of synaptic connections (excitatory or inhibitory) is determined by the charge of the ions that flow through these channels. In general, channels that conduct positive ions are excitatory, whereas channels that conduct negative ions are inhibitory. 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 and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family.

                          10        20        30
                  ....*....|....*....|....*....|....
gi 1315144612 284 YFMIQTYIPCIMTVILSQVSFWINKESVPARTVF 317
Cdd:cd19052     1 YFVIQTYLPCIMTVILSQVSFWLNKESVPARTVF 34

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 1315144612  13 CSGVSLALLHFLCLAACLNESPGQNSKDEKLcpenfTRILDSLLDGYDNRLRPGFGGTdcfktckcalsvrlwsaclfve 92
Cdd:TIGR00860   1 LSQILLALLLFASLAAVSLAGNAKSNLKEVE-----RKLLDELLKNYDARVRPVFGGP---------------------- 53

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  93 ilgPVTeVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDgPIEILRLNNMMV--TKVWTPDTFFRNGKKSVSHN 170
Cdd:TIGR00860  54 ---PVT-VSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWN-PEEYPGVTLVRTpdDSIWVPDIFFYNEKDARFHG 128

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 171 MTAPNKLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTW-TKGPEKSVEvpKESSSLVQ 249
Cdd:TIGR00860 129 ITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKLEWkEQGAVQVDD--SLFISLPE 206

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1315144612 250 YDLIGQTVS-SETIKSITGEYIVMTVYFHLRRKMGYFMIQTYIPCIMTVILSQVSFWINKESVPAR 314
Cdd:TIGR00860 207 FELLGVYGTrYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADASGAR 272

transmembrane domain of alpha subunits of type-A gamma-aminobutyric acid receptor (GABAAR); 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
                  ....*....|....*....|....*....|....
gi 1315144612 284 YFMIQTYIPCIMTVILSQVSFWINKESVPARTVF 317
Cdd:cd19052     1 YFVIQTYLPCIMTVILSQVSFWLNKESVPARTVF 34

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 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKL 177
Cdd:cd18998     1 TEVKTDIYVTSFGPVSDVDMEYTIDVFFRQTWKDERLKFKGPMKILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 178 FRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGPEKSVEVPKESSSLVQYDLIGQTV 257
Cdd:cd18998    81 LRIQDDGTLLYTMRLTIHAECPMHLEDFPMDAHSCPLKFGSYAYPKSEVVYTWTYGPKKSVEVAEDGSRLNQYDLIGQTV 160

                         170       180
                  ....*....|....*....|....
gi 1315144612 258 SSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd18998   161 GSETIKSSTGEYVVMTVHFHLKRK 184

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 1315144612  56 LDGYDNRLRPGFGGTdcfktckcalsvrlwsaclfveilgpVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLK 135
Cdd:cd19036     1 LDGYDNRLRPGLGDS--------------------------VTEVKTDIYVTSFGPVSDTDMEYTIDVFFRQSWRDERLK 54

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 136 YDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLK 215
Cdd:cd19036    55 FDGPMKILPLNNLLASKIWTPDTFFHNGKKSVAHNMTTPNKLLRLVDNGTLLYTMRLTIHAECPMHLEDFPMDVHACPLK 134

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1315144612 216 FGSYAYPKSEMIYTWTKGPEKSVEVPKESSSLVQYDLIGQTVSSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19036   135 FGSYAYTKTEVVYSWTLGKNKSVEVAPDGSRLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLKRK 200

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5 or GABRA5); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5), a protein that is encoded by the GABRA5 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-5 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha5-beta-gamma2, and probably alpha5-beta3-gamma2, predominantly expressed in the hippocampus and localized extrasynaptically. These receptors have been demonstrated to play an important modulatory role in learning and memory processes, thus making them suitable targets for pharmacological intervention. Studies show that alpha5-containing GABAARs play an important part in tonic inhibition in hippocampal pyramidal neurons, and that these can also contribute to synaptic inhibition. Studies strongly suggest that amnesia is primarily mediated by alpha5-beta-gamma2. Polymorphisms in GABRA5 (and GABRA3) are linked to the susceptibility to panic disorder. A genetic association also exists between GABRA5 and bipolar affective disorder.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  57 DGYDNRLRPGFGGTdcfktckcalsvrlwsaclfveilgpVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKY 136
Cdd:cd19038     1 DGYDNRLRPGLGER--------------------------ITQVRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRF 54

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 137 DGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKF 216
Cdd:cd19038    55 KGPMQRLPLNNLLASKIWTPDTFFHNGKKSIAHNMTTPNKLLRLEDDGTLLYTMRLTISAECPMQLEDFPMDAHACPLKF 134

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1315144612 217 GSYAYPKSEMIYTWTKGPEKSVEVPKESSSLVQYDLIGQTVSSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19038   135 GSYAYPNSEVVYVWTNGTTKSVVVAEDGSRLNQYHLMGQTVGTENISTSTGEYTIMTAHFHLKRK 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 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDG-PIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNK 176
Cdd:cd19007     2 TTVETDILIRSMGPISELDMTYSMDCYFRQSWQDRRLAFNGpSIDTLSLSIKMLDRIWKPDTYFYNGKKSYLHTITTPNK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 177 LFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGpeKSVEVpKESSSLVQYDLIGQT 256
Cdd:cd19007    82 LVRLRQDGRILYSMRLTIKASCPMNLEKFPMDTQSCPLIIGSYGYTTKDVIYKWKDG--RDVVI-APDMTLSQFDLVGFP 158

                         170       180
                  ....*....|....*....|....
gi 1315144612 257 VSSETIKSITGEYIVMTVYFHLRR 280
Cdd:cd19007   159 AGNVTDIRRGGNYSMLSVNFHLQR 182

gamma-aminobutyric acid receptor extracellular domain; 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 heteropentameric GABAARs, and 3 rho subunits that only form homopentameric channels (also known as GABAA rho or GABAC receptor) or pseudoheteromeric if consisting of different rho subunits. The majority of GABAA receptor pentamers contain two alpha subunits, two beta subunits, and a gamma subunit, with different isoforms affecting potency of the neurotransmitter. 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. Specific combinations of alpha, beta, and gamma subunits exhibit ethanol sensitivity. All these major classes of drugs favor channel-opening. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYD--GPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPN 175
Cdd:cd18990     1 VVVTVEIWVQSIGSISEINMDFTLDIYFRQYWRDPRLAFDhnGCNKNLTLSGEMLSKIWTPDTFFVNSKKAKFHDVTTPN 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 176 KLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGPEKSVEVPKEssSLVQYDLIGQ 255
Cdd:cd18990    81 ILLRIYPNGTVLYSYRLTVTAPCSMDLRKFPMDTQTCSLVFESYGYTTDDVVYKWKEGDTPVTILEKI--ELPQFDLTGV 158

                         170       180
                  ....*....|....*....|....*
gi 1315144612 256 TVSSETIKSITGEYIVMTVYFHLRR 280
Cdd:cd18990   159 TTSEKTEVYPAGNYSRLTVTFTFKR 183

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 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKL 177
Cdd:cd19044     3 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRM 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 178 FRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKgpeKSVEVPKESS-SLVQYDLIGQT 256
Cdd:cd19044    83 LRIWNDGRVLYTLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKR---SSVEVGDTRSwRLYQFSFVGLR 159

                         170       180
                  ....*....|....*....|....*
gi 1315144612 257 VSSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19044   160 NTTEVVKTTSGDYVVMSVYFDLSRR 184

extracellular domain of gamma-aminobutyric acid receptor subunit gamma-3 (GABAAR-G3 or GABRG3); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-3 (GABAAR-G3), a protein that is encoded by the GABRG3 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-3 subunit forms heteropentamers with other GABAAR subunits, likely expressed as alpha1-beta3-gamma3. This subunit contains the benzodiazepine binding site. Polymorphisms in GABG3 show consistent evidence of alcohol dependence.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKL 177
Cdd:cd19045     1 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 178 FRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKgpeKSVEVPKESS-SLVQYDLIGQT 256
Cdd:cd19045    81 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRK---NSVEAADQKSwRLYQFDFMGLR 157

                         170       180
                  ....*....|....*....|....*
gi 1315144612 257 VSSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19045   158 NTTEIVTTSAGDYVVMTIYFELSRR 182

extracellular domain of gamma-aminobutyric acid receptor subunit epsilon (GABRE); This family contains extracellular domain of epsilon subunit of type-A gamma-aminobutyric acid receptor (GABAAR), a protein that is encoded by the GABRE 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 epsilon subunits form heteropentamers with other GABAAR subunits, possibly with alpha3, beta4, and theta subunits since their genes are clustered on the same human chromosome. Various combinations of alpha3-, theta-, and epsilon-subunits may be assembled at a regional and developmental level in the brain. Brainstem expression of epsilon subunit-containing GABAA receptors is upregulated during pregnancy, particularly in the ventral respiratory neurons, thus protecting breathing, despite increased neurosteroid levels during pregnancy.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKL 177
Cdd:cd19002     1 TVVTVEISVNSLGPLSILDMEYTIDIIFSQTWYDERLRYNDTFESLVLNGNVVSQLWIPDTFFRNSKRTHEHEITMPNQM 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 178 FRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGPEKSVEvpKESSSLVQYDLIGQTV 257
Cdd:cd19002    81 VRIHKDGKVLYTIRMTIDAGCSLHMLRFPMDSHSCPLSFSSFSYPENEMIYKWENFKLEINE--KNSWKLFQFDFTGVSN 158

                         170       180
                  ....*....|....*....|....
gi 1315144612 258 SSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19002   159 KTEIITTPVGDFMVMTIFFNVSRR 182

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 1315144612  98 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDG--PIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPN 175
Cdd:cd18991     2 TNVSVQIYINSIDSINEATMDYSVNIFLRQRWNDPRLNFTKlsNIDYLELDPKMIDKIWVPDLFFPNEKKANFHDVTVPN 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 176 KLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTkgPEKSVEVPKEsSSLVQYDLIGQ 255
Cdd:cd18991    82 KLLRIYPNGTVYYSMRLSLTLSCPMDLHKYPLDTQTCPIQIESFGYTTENLIFKWN--DDKPVQLNDG-LELPQFELKGV 158

                         170       180
                  ....*....|....*....|....*.
gi 1315144612 256 TVSS-ETIKSITGEYIVMTVYFHLRR 280
Cdd:cd18991   159 STSDcTKTYTETGNFSCLEAKFHLQR 184

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 1315144612  99 EVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGP--IEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNK 176
Cdd:cd19008     2 EVGVTMYVLSISSVSEVDMDFTLDFYFRQFWTDPRLAFKKSpgVESLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSNE 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 177 LFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGPeKSVEVpKESSSLVQYDLIGQT 256
Cdd:cd19008    82 FLRIHHSGSITRSIRLTITASCPMNLQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGP-NSVGI-SPEVELPQFKVLGHR 159

                         170       180
                  ....*....|....*....|....
gi 1315144612 257 VSSETIKSITGEYIVMTVYFHLRR 280
Cdd:cd19008   160 QRAREISLTTGNYSRLACEIQFVR 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 1315144612 100 VKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKLFR 179
Cdd:cd19003     4 VRISIYVSSIEQISEMNMDYTITMFFHQTWKDSRLAYYETTLNLTLDYRMHEKLWVPDCYFLNSKDAFVHDVTVENRVFQ 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 180 IMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWtKGPEKSVEVpKESSSLVQYDLIGQTVSS 259
Cdd:cd19003    84 LHPDGTVRYGIRLTTTAACSLDLHKFPMDKQACKLEVESYGYTVEDIILFW-EDNGNAIHM-TEELHIPQFTFLGRTITS 161

                         170       180
                  ....*....|....*....|..
gi 1315144612 260 ETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd19003   162 KEVYFYTGSYIRLILKFQVQRE 183

extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 100 VKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYD----GPIEILRLNNmmvTKVWTPDTFFRNGKKSvsHNMTAPN 175
Cdd:cd03558     3 VTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSpadyGGVDSLRLPS---EQIWLPDLVFYNNKDA--DFVTTDN 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 176 KLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWtkgpEKSVEVPKESSSLVQYDLIGQ 255
Cdd:cd03558    78 VLIRLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIELVW----DSERPDQADFLELPEWDIVEK 153

                         170       180
                  ....*....|....*....|....*.
gi 1315144612 256 TVSSETIKSITGEYIVMTVYFHLRRK 281
Cdd:cd03558   154 RGRYCTVVYNTGIYSDITYRFRLKRQ 179

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  96 PVTeVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPiEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPN 175
Cdd:cd19004     1 PVT-VGMSLDIASIDTISEINMDYTATIFLRQRWTDERLCFEGN-KSLSLDGRLVELLWVPDTFIVDSKKSFLHDITVEN 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 176 KLFRIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGpEKSVEvPKESSSLVQYDLIGQ 255
Cdd:cd19004    79 RLIRIFPNGTVLYALRITTTVACSMDLTKYPMDKQTCTLQLESWGYNINDVMFYWTRG-NDSVR-GLDHLRLAQYTVEDY 156

                         170       180
                  ....*....|....*....|....*
gi 1315144612 256 TVSSETIKSITGEYIVMTVYFHLRR 280
Cdd:cd19004   157 FTSVSEAVYETGNYPKLVFHFELKR 181

extracellular domain of gamma-aminobutyric acid receptor subunit beta-1 (GABAAR-B1 or GABRB1); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-1 subunit, a protein that is encoded by the GABRB1 gene. 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 beta-1 subunit forms heteropentamers with other GABAAR subunits, likely expressed as alpha-beta1-gamma/delta, mainly found in the brain. It is clustered on the chromosome with genes encoding alpha 4, alpha 2, and gamma 1 subunits of the GABAAR. GABRB1 expression is altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression, and bipolar disorder. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition. Epigenetic control of gene expression may affect the expression of GABRB1 and disrupt inhibitory synaptic transmission during embryonic development. The GABRB1 gene is also associated with thalamus volume and modulates the association between thalamus volume and intelligence.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612  99 EVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLNNMMVTKVWTPDTFFRNGKKSVSHNMTAPNKLF 178
Cdd:cd19040     2 DVGMRIDVASIDMVSEVNMDYTLTMYFQQSWRDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMI 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315144612 179 RIMRNGTILYTMRLTISAECPMRLVDFPMDGHACPLKFGSYAYPKSEMIYTWTKGPEKSVEVpkESSSLVQYDLIGQTVS 258
Cdd:cd19040    82 RLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGV--NKIELPQFSIIDYKMV 159

                         170       180
                  ....*....|....*....|..
gi 1315144612 259 SETIKSITGEYIVMTVYFHLRR 280
Cdd:cd19040   160 SKKVEFTTGAYPRLSLSFRLKR 181