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 153792343    1 MVLLLPWLFIILWLENAQAQLEDEGNFySENVSRILDNLLEGYDNRLRPGFGGAVTEVKTDIYVTSFGPVSDVEMEYTMD 80
Cdd:TIGR00860   1 LSQILLALLLFASLAAVSLAGNAKSNL-KEVERKLLDELLKNYDARVRPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTN 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343   81 VFFRQTWTDERLKFkGPAEILSLNNLMV--SKIWTPDTFFRNGKKSIAHNMTTPNKLFRLMQNGTILYTMRLTINADCPM 158
Cdd:TIGR00860  80 IWLRQEWTDERLQW-NPEEYPGVTLVRTpdDSIWVPDIFFYNEKDARFHGITMTNVLVRIHPNGSVLYSPRITLTLACPM 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  159 RLVNFPMDGHACPLKFGSYAYPKTEIIYTWK-KGPLYSVEvpEESSSLLQYDLIGQTVS-SETIKSNTGEYVIMTVYFHL 236
Cdd:TIGR00860 159 DLRNFPFDVQNCSLKFESWGYTTNDIKLEWKeQGAVQVDD--SLFISLPEFELLGVYGTrYCTSETNTGEYPCLTFSFVL 236

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  237 QRKMGYFMIQIYTPCIMTVILSQVSFWINKESVPARTVFGITTVLTMTTLSISARHSLPKVSYATAMDWFIAVCFAFVFS 316
Cdd:TIGR00860 237 RRRPLYYLLQLYIPSILIVILSWVSFWLPADASGARVSLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFL 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  317 ALIEFAAVNYFTNLQSQKA------ERQA--------QTAATPPV--AKSKASESLQAEIVVHSDSKYHLKKRISSLTLP 380
Cdd:TIGR00860 317 ALLETAFVNYVHHKDPAQGkrhlllERCAwrlckqepGEDYRRPAldHASLSSVEMRAKDGGRGLESPTERQRLLHSPPP 396

                         410       420       430       440       450       460
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 153792343  381 IVPSSEASKALSRTPIL-------KSTPVSPPLLLPAtggtSKIDQYSRILFPVAFAGFNLVYWIVY 440
Cdd:TIGR00860 397 AEGDLDLAGILEEVRIAhrfrkrdESEEVVRDWKFRA----KVIDKLSRMAFPLAFLLFNIGYWMSY 459

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 153792343    1 MVLLLPWLFIILWLENAQAQLEDEGNFySENVSRILDNLLEGYDNRLRPGFGGAVTEVKTDIYVTSFGPVSDVEMEYTMD 80
Cdd:TIGR00860   1 LSQILLALLLFASLAAVSLAGNAKSNL-KEVERKLLDELLKNYDARVRPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTN 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343   81 VFFRQTWTDERLKFkGPAEILSLNNLMV--SKIWTPDTFFRNGKKSIAHNMTTPNKLFRLMQNGTILYTMRLTINADCPM 158
Cdd:TIGR00860  80 IWLRQEWTDERLQW-NPEEYPGVTLVRTpdDSIWVPDIFFYNEKDARFHGITMTNVLVRIHPNGSVLYSPRITLTLACPM 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  159 RLVNFPMDGHACPLKFGSYAYPKTEIIYTWK-KGPLYSVEvpEESSSLLQYDLIGQTVS-SETIKSNTGEYVIMTVYFHL 236
Cdd:TIGR00860 159 DLRNFPFDVQNCSLKFESWGYTTNDIKLEWKeQGAVQVDD--SLFISLPEFELLGVYGTrYCTSETNTGEYPCLTFSFVL 236

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  237 QRKMGYFMIQIYTPCIMTVILSQVSFWINKESVPARTVFGITTVLTMTTLSISARHSLPKVSYATAMDWFIAVCFAFVFS 316
Cdd:TIGR00860 237 RRRPLYYLLQLYIPSILIVILSWVSFWLPADASGARVSLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFL 316

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  317 ALIEFAAVNYFTNLQSQKA------ERQA--------QTAATPPV--AKSKASESLQAEIVVHSDSKYHLKKRISSLTLP 380
Cdd:TIGR00860 317 ALLETAFVNYVHHKDPAQGkrhlllERCAwrlckqepGEDYRRPAldHASLSSVEMRAKDGGRGLESPTERQRLLHSPPP 396

                         410       420       430       440       450       460
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 153792343  381 IVPSSEASKALSRTPIL-------KSTPVSPPLLLPAtggtSKIDQYSRILFPVAFAGFNLVYWIVY 440
Cdd:TIGR00860 397 AEGDLDLAGILEEVRIAhrfrkrdESEEVVRDWKFRA----KVIDKLSRMAFPLAFLLFNIGYWMSY 459

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        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 242 YFMIQIYTPCIMTVILSQVSFWINKESVPARTVFGITTVLTMTTLSISARHSLPKVSYATAMDWFIAVCFAFVFSALIEF 321
Cdd:cd19052    1 YFVIQTYLPCIMTVILSQVSFWLNKESVPARTVFGVTTVLTMTTLSISARNSLPKVSYATAMDWFIAVCFAFVFSALIEF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 322 AAVNYFtnlqsqkaerqaqtaatppvakskaseslqaeivvhsdskyhlkkrissltlpivpsseaskalsrtpilkstp 401
Cdd:cd19052   81 ATVNYF-------------------------------------------------------------------------- 86

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 153792343 402 vspplllpatgGTSKIDQYSRILFPVAFAGFNLVYW 437
Cdd:cd19052   87 -----------GTSKIDKYSRILFPVLFGIFNLVYW 111

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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKL 135
Cdd:cd18998    1 TEVKTDIYVTSFGPVSDVDMEYTIDVFFRQTWKDERLKFKGPMKILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 136 FRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLYSVEVPEESSSLLQYDLIGQTV 215
Cdd:cd18998   81 LRIQDDGTLLYTMRLTIHAECPMHLEDFPMDAHSCPLKFGSYAYPKSEVVYTWTYGPKKSVEVAEDGSRLNQYDLIGQTV 160

                        170       180
                 ....*....|....*....|....
gi 153792343 216 SSETIKSNTGEYVIMTVYFHLQRK 239
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 153792343  40 LEGYDNRLRPGFGGAVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFR 119
Cdd:cd19036    1 LDGYDNRLRPGLGDSVTEVKTDIYVTSFGPVSDTDMEYTIDVFFRQSWRDERLKFDGPMKILPLNNLLASKIWTPDTFFH 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 120 NGKKSIAHNMTTPNKLFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLYSVEVP 199
Cdd:cd19036   81 NGKKSVAHNMTTPNKLLRLVDNGTLLYTMRLTIHAECPMHLEDFPMDVHACPLKFGSYAYTKTEVVYSWTLGKNKSVEVA 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 153792343 200 EESSSLLQYDLIGQTVSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19036  161 PDGSRLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLKRK 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 153792343  37 DNLLEGYDNRLRPGFGGAVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDT 116
Cdd:cd19035    1 DRLLDGYDNRLRPGLGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQRWKDERLKFKGPMNILRLNNLMASKIWTPDT 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 117 FFRNGKKSIAHNMTTPNKLFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLYSV 196
Cdd:cd19035   81 FFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSCPLKFGSYAYTTSEVTYIWTYNASDSV 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 153792343 197 EVPEESSSLLQYDLIGQTVSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19035  161 QVAPDGSRLNQYDLLGQTIGKETIKSSTGEYTVMTAHFHLKRK 203

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1 or GABRA1); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1), a protein that is encoded by the GABRA1 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-1 subunits form heteropentamers with other GABAAR subunits, most broadly expressed as combination of two alpha1, beta1, gamma. Alpha1, beta2, and gamma2 subunits are clustered on the same human chromosome and may be why alpha1beta2gamma2 receptors are one of the most abundant GABAA receptor isoforms in CNS neurons. Mutations in this gene cause familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy type 4, and idiopathic familial generalized epilepsy. Polymorphisms in GABRA1 are also significantly associated with schizophrenia. GABRA1 has also been associated with methamphetamine abuse. The GABRA1 receptor is the specific target of the z-drug class of nonbenzodiazepine hypnotic agents and is responsible for their hypnotic and hallucinogenic effects.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  46 RLRPGFGGAVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSI 125
Cdd:cd19034    1 RLRPGLGERVTEVKTDIFVTSFGPVSDHDMEYTIDVFFRQSWKDERLKFKGPMTVLRLNNLMASKIWTPDTFFHNGKKSV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 126 AHNMTTPNKLFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLYSVEVPEESSSL 205
Cdd:cd19034   81 AHNMTMPNKLLRITEDGTLLYTMRLTVRAECPMHLEDFPMDAHACPLKFGSYAYTRAEVVYEWTREPARSVVVAEDGSRL 160

                        170       180       190
                 ....*....|....*....|....*....|....
gi 153792343 206 LQYDLIGQTVSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19034  161 NQYDLLGQTVDSGIVQSSTGEYVVMTTHFHLKRK 194

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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKL 135
Cdd:cd19000    1 TVIHTDMYVNSIGPVNAINMEYTIDIFFAQTWYDSRLKFNSTMKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 136 FRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGplySVEVPEESS-SLLQYDLIGQT 214
Cdd:cd19000   81 LRIWNDGRVLYTLRLTINAECQLQLHNFPMDEHSCPLEFSSYGYPKEEIIYKWKKS---SVEVADQKSwRLYQFSFVGLR 157

                        170       180
                 ....*....|....*....|....*
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19000  158 NTTEIVKTTSGDYVVMTIYFDLSRR 182

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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKL 135
Cdd:cd19043    1 TVIETDVYVNSIGPVDPINMEYTIDIIFAQTWFDSRLKFNSTMKVLMLNSNMVGKIWIPDTFFRNSRKSDAHWITTPNRL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 136 FRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGplySVEVPEESS-SLLQYDLIGQT 214
Cdd:cd19043   81 LRIWSDGRVLYTLRLTINAECYLQLHNFPMDEHSCPLEFSSYGYPKNEIEYKWKKP---SVEVADPKYwRLYQFAFVGLR 157

                        170       180
                 ....*....|....*....|....*
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19043  158 NSTEISHTISGDYIIMTIFFDLSRR 182

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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKL 135
Cdd:cd19045    1 TVIDVDIYVNSIGPVSSINMEYQIDIFFAQTWTDSRLRFNSTMKILTLNSNMVGLIWIPDTIFRNSKTAEAHWITTPNQL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 136 FRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGplySVEVPEESS-SLLQYDLIGQT 214
Cdd:cd19045   81 LRIWNDGKILYTLRLTINAECQLQLHNFPMDEHSCPLIFSSYGYPKEEMIYRWRKN---SVEAADQKSwRLYQFDFMGLR 157

                        170       180
                 ....*....|....*....|....*
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQRK 239
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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKL 135
Cdd:cd19002    1 TVVTVEISVNSLGPLSILDMEYTIDIIFSQTWYDERLRYNDTFESLVLNGNVVSQLWIPDTFFRNSKRTHEHEITMPNQM 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 136 FRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKgplYSVEVPEESS-SLLQYDLIGQT 214
Cdd:cd19002   81 VRIHKDGKVLYTIRMTIDAGCSLHMLRFPMDSHSCPLSFSSFSYPENEMIYKWEN---FKLEINEKNSwKLFQFDFTGVS 157

                        170       180
                 ....*....|....*....|....*
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19002  158 NKTEIITTPVGDFMVMTIFFNVSRR 182

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 153792343  56 TEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGPAEI--LSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPN 133
Cdd:cd18987    1 TNVKVSIYIESISSIDEQTMDFTVDMYLRQRWTDPRLAYPDRNGTdpILLPSDKFDKIWLPDLYFRNEKSSSFHDVTTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 134 KLFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPlySVEVPEESSSLLQYDLIGQ 213
Cdd:cd18987   81 VLVRIFPNGTVLYSQRLTLTLSCPMNLQKFPFDTQVCTLRLESYGYTTDQVVLHWDDDP--PIVVNESSLLLPEFSLVKI 158

                        170       180
                 ....*....|....*....|....*.
gi 153792343 214 TVSSETIK-SNTGEYVIMTVYFHLQR 238
Cdd:cd18987  159 TTSDCTGNySTTGNYSCLEATFKLKR 184

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 153792343  247 IYTPCIMTVILSQVSFWINKESVPARTVFGITTVLTMTTLSISARHSLPKVSYATAMDW-FIAVCFAFVFSALIEFAAVN 325
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAVGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGkYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  326 YFTNLQSQKAERQA-----------------QTAATPPVAKSKASESLQAEIVVHSDSKYHLKKRISS------------ 376
Cdd:pfam02932  81 NVHHRSPSTHKMPPwvrkifleklprllgmkRPPEAPPPPASPGYGSKAEEYILRKPRSELPFEKQSErhglgrettcsy 160

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 153792343  377 -------LTLPIVPSSEASKALSRT----PILKSTPVSPPLLLPATGGTSKIDQYSRILFPVAFAGFNLVYW 437
Cdd:pfam02932 161 gcslgngSSQPRELSPELKKAVEGVnfiaKHLRSQDEYISVKEDWKYVAMVIDRLSRWIFPIAFVLGTLGYF 232

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 153792343  57 EVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKGP--AEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNK 134
Cdd:cd19008    2 EVGVTMYVLSISSVSEVDMDFTLDFYFRQFWTDPRLAFKKSpgVESLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSNE 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 135 LFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLySVEVPEEsSSLLQYDLIGQT 214
Cdd:cd19008   82 FLRIHHSGSITRSIRLTITASCPMNLQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGPN-SVGISPE-VELPQFKVLGHR 159

                        170       180
                 ....*....|....*....|....
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQR 238
Cdd:cd19008  160 QRAREISLTTGNYSRLACEIQFVR 183

extracellular domain of glycine receptor alpha subunit; This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) alpha subunits of the amino acid neurotransmitter glycine. GlyR has four known isoforms of alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands, and, along with the GlyR beta subunit, have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). These alpha subunits are highly homologous, but differ in their kinetic properties, temporal and regional expression and physiological functions. They can form functional chloride-permeable GlyR ion channels by forming homopentamers with 5 alpha subunits or heteropentamers with a combination of alpha and beta subunits, either a 2alpha-3beta or 3alpha-2beta stoichiometry. In human, mutations in glycine receptor alpha subunits cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions. Mutations in GlyR alpha1 subunit leads to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli, while 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. GlyR alpha1 and alpha2 subunits have an important role in regulation of the excitatory-inhibitory balance, control of motor actions, modulation of sedative ethanol effects and probably regulation ethanol preference and consumption.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343  58 VKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFKG-PAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNKLF 136
Cdd:cd19009    4 VTCNIFINSFGSIAETTMDYRVNIFLRQQWNDPRLAYSEyPDDSLDLDPSMLDSIWKPDLFFANEKGANFHEVTTDNKLL 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 137 RLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWK-KGPlysVEVPeESSSLLQYDLIGQ-T 214
Cdd:cd19009   84 RISKNGNVLYSIRLTLTLACPMDLKNFPMDVQTCIMQLESFGYTMNDLIFEWQeKGP---VQVA-DGLTLPQFILKEEkD 159

                        170       180
                 ....*....|....*....|....*
gi 153792343 215 VSSETIKSNTGEYVIMTVYFHLQRK 239
Cdd:cd19009  160 LRYCTKHYNTGKFTCIEVRFHLERQ 184

gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such as LCCH3 (ligand-gated chloride channel homolog 3); This family contains extracellular domain of beta-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster ligand-gated chloride channel homolog 3 (LCCH3) 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 coexpressed 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 153792343  57 EVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKF--KGPAEILSLNNLMVSKIWTPDTFFRNGKKSIAHNMTTPNK 134
Cdd:cd19006    3 LVGMDLTIASFDSISEVNMDYTITMYLNQYWKDERLAFsiDNESDVLTLSGDFAEKIWVPDTFFANDKNSFLHDVTERNK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153792343 135 LFRLMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYPKTEIIYTWKKGPLYSVevpeESSSLLQYDLIGQT 214
Cdd:cd19006   83 MVRLNGDGSITYGMRFTTTLACMMDLHYYPLDSQNCTVEIESYGYTVSDVVMYWKNTPVRGV----EDAELPQFTIIGYE 158