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        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19057    1 FNAFQNYVPSSVTTMLSWVSFWIKKESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 80

                 ....*...
gi 768039875 137 AVLNFLIY 144
Cdd:cd19057   81 AVLNFLIH 88

transmembrane domain of epsilon subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of type-A gamma-aminobutyric acid receptor (GABAAR) subunits as well as glycine receptor (GlyR). 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 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19057    1 FNAFQNYVPSSVTTMLSWVSFWIKKESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 80

                 ....*...
gi 768039875 137 AVLNFLIY 144
Cdd:cd19057   81 AVLNFLIH 88

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 768039875    2 IYKWENFKLEINEKNSWKLFQFDFTGV---SNKTEIITTpvGDFMVMTIFFNVSRRFGYVAFQNYVPSSVTTMLSWVSFW 78
Cdd:TIGR00860 186 LEWKEQGAVQVDDSLFISLPEFELLGVygtRYCTSETNT--GEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFW 263

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875   79 IKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEFAVLNFLiynqtkAHASPKLRHp 158
Cdd:TIGR00860 264 LPADASGARVSLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFLALLETAFVNYV------HHKDPAQGK- 336

                         170       180
                  ....*....|....*....|....
gi 768039875  159 rinsRAHARTRARSRACARQHQEA 182
Cdd:TIGR00860 337 ----RHLLLERCAWRLCKQEPGED 356

transmembrane domain of epsilon subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of type-A gamma-aminobutyric acid receptor (GABAAR) subunits as well as glycine receptor (GlyR). 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 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19057    1 FNAFQNYVPSSVTTMLSWVSFWIKKESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 80

                 ....*...
gi 768039875 137 AVLNFLIY 144
Cdd:cd19057   81 AVLNFLIH 88

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 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19054    1 YFTIQTYIPCILTVVLSWVSFWINKDAVPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFAALMEY 80

                 ....*.
gi 768039875 137 AVLNFL 142
Cdd:cd19054   81 GTLHYF 86

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 768039875    2 IYKWENFKLEINEKNSWKLFQFDFTGV---SNKTEIITTpvGDFMVMTIFFNVSRRFGYVAFQNYVPSSVTTMLSWVSFW 78
Cdd:TIGR00860 186 LEWKEQGAVQVDDSLFISLPEFELLGVygtRYCTSETNT--GEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFW 263

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875   79 IKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEFAVLNFLiynqtkAHASPKLRHp 158
Cdd:TIGR00860 264 LPADASGARVSLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFLALLETAFVNYV------HHKDPAQGK- 336

                         170       180
                  ....*....|....*....|....
gi 768039875  159 rinsRAHARTRARSRACARQHQEA 182
Cdd:TIGR00860 337 ----RHLLLERCAWRLCKQEPGED 356

transmembrane domain of beta subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the beta subunit of type-A beta-aminobutyric acid receptor (GABAAR), which includes beta1-beta4 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. Mutations or genetic variations of the genes encoding beta2 (GABRB2) and beta3 (GABRB3) have been associated with human epilepsy, both with and without febrile seizures. Mutations in GABRB2, and GABRB3 have been associated with infantile spasms and Lennox-Gastaut syndrome. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy, a disease with a devastating prognosis, characterized by neonatal onset of seizures. Another de novo heterozygous missense variant in exon 4 of GABRB2 is associated with intellectual disability and epilepsy. Mutations in the GABRB1 gene encoding beta1 promote alcohol consumption through increased tonic inhibition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19053    1 YFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIPYVKAIDMYLMGCFVFVFLALLEY 80

                 ....*....
gi 768039875 137 AVLNFLIYN 145
Cdd:cd19053   81 AFVNYIDVN 89

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 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd19052    1 YFVIQTYLPCIMTVILSQVSFWLNKESVPARTVFGVTTVLTMTTLSISARNSLPKVSYATAMDWFIAVCFAFVFSALIEF 80

                 ....*
gi 768039875 137 AVLNF 141
Cdd:cd19052   81 ATVNY 85

transmembrane domain of delta subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the delta subunit of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the gene GABRD. 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. Receptors containing the delta subunit (GABRD) are expressed exclusively extra-synaptically (in the cortex, hippocampus, thalamus, striatum, and cerebellum) and mediate tonic inhibition. Studies suggest that delta subunits form heteropentamers in similar stoichiometry and arrangement as alpha/beta/gamma receptors, with the delta subunit replacing the gamma subunit (2alpha:2beta:1delta), although other stoichiometries have also been detected. The delta subunit is flexible in its positioning in the pentameric complex, producing receptors with diverse pharmacological properties. Mutations in GABRD have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. GABRD gene may also be associated with childhood-onset mood disorders.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875  61 QNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEFAVLN 140
Cdd:cd19055    5 QSYMPSILLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSSLPRASAIKALDVYFWICYVFVFAALVEYAFAH 84

                 .
gi 768039875 141 F 141
Cdd:cd19055   85 Y 85

transmembrane domain of pi subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the pi subunit of type-A gamma-aminobutyric acid receptor (GABAAR), encoded my the gene GABRP. 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. 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 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVS-YITALDFYIAICFVFCFCALLE 135
Cdd:cd19058    2 YFILETYVPSTLLVVLSWVSFWISLSSVPARTCIGVTTVLSMTTLMMGSRTSLPNANcFIKAIDVYLGICFSFIFGALLE 81

                 ....*.
gi 768039875 136 FAVLNF 141
Cdd:cd19058   82 YAVAHY 87

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        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768039875  57 YVAFQNYVPSSVTTMLSWVSFWIKTESApARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 136
Cdd:cd03559    1 YYAVSLLLPSILIMVVSWVGFWLPPDSG-ERVSFKITLLLTYSVFLIIVSDTLPATPYTPLIDVYFVVCMALLFIALLET 79

                         90
                 ....*....|
gi 768039875 137 AVLNFLIYNQ 146
Cdd:cd03559   80 IFIVRLVHKQ 89

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
                 ....*....|....*....|....*....|....*....|....*....|....
gi 768039875   1 MIYKWENFKLEINEKNSWKLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRR 54
Cdd:cd19045  129 MIYRWRKNSVEAADQKSWRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSRR 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
                 ....*....|....*....|....*....|....*....|....*....|....
gi 768039875   1 MIYKWENFKLEINEKNSWKLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRR 54
Cdd:cd19044  131 IVYQWKRSSVEVGDTRSWRLYQFSFVGLRNTTEVVKTTSGDYVVMSVYFDLSRR 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
                 ....*....|....*....|....*....|....*....|....*....|..
gi 768039875   3 YKWENFKLEINEKNSWKLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRR 54
Cdd:cd19043  131 YKWKKPSVEVADPKYWRLYQFAFVGLRNSTEISHTISGDYIIMTIFFDLSRR 182

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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 768039875   1 MIYKWEN---FKLEINEKNSwKLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRR 54
Cdd:cd19039  143 IVYTWKKgplYSVEVPEESS-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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 768039875   1 MIYKW---ENFKLEINEKNSwKLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRR 54
Cdd:cd19036  145 VVYSWtlgKNKSVEVAPDGS-RLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLKRK 200