transmembrane domain of anionic Cys-loop neurotransmitter-gated ion channels, includes GABAAR, GlyR and GluCl; This family contains transmembrane domain of type-A gamma-aminobutyric acid receptor (GABAAR) as well as glycine receptor (GlyR) subunits. Thus far, there are 18 vertebrate receptor subunits categorized in 7 families: alpha1-6, beta1-4, gamma1-4, delta, epsilon, theta, rho, and pi. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GlyR, with a similar structure as GABAAR, is concentrated in the brain stem and spinal cord in the CNS and can be activated by glycine, beta-alanine, or taurine. It is selectively blocked by the high-affinity competitive antagonist strychnine, which causes death by asphyxiation. An autosomal dominant R271Q mutation in GLRA1 causes hyperekplexia (Startle disease or Stiff Baby Syndrome) by decreasing glycine sensitivity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd19049     1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                          90       100
                  ....*....|....*....|....*
gi 1831511399 161 AAVGYISKRmklvRARKESRMLTPL 185
Cdd:cd19049    81 AVVNYLKAS----KIDRISRILFPL 101

transmembrane domain of anionic Cys-loop neurotransmitter-gated ion channels, includes GABAAR, GlyR and GluCl; This family contains transmembrane domain of type-A gamma-aminobutyric acid receptor (GABAAR) as well as glycine receptor (GlyR) subunits. Thus far, there are 18 vertebrate receptor subunits categorized in 7 families: alpha1-6, beta1-4, gamma1-4, delta, epsilon, theta, rho, and pi. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GlyR, with a similar structure as GABAAR, is concentrated in the brain stem and spinal cord in the CNS and can be activated by glycine, beta-alanine, or taurine. It is selectively blocked by the high-affinity competitive antagonist strychnine, which causes death by asphyxiation. An autosomal dominant R271Q mutation in GLRA1 causes hyperekplexia (Startle disease or Stiff Baby Syndrome) by decreasing glycine sensitivity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd19049     1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                          90       100
                  ....*....|....*....|....*
gi 1831511399 161 AAVGYISKRmklvRARKESRMLTPL 185
Cdd:cd19049    81 AVVNYLKAS----KIDRISRILFPL 101

transmembrane domain of alpha subunits of glycine receptor (GlyR); This family contains transmembrane (TM) domain of the alpha subunit of glycine receptor (GlyR or GLR) of the amino acid neurotransmitter glycine. 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. GlyR has four known isoforms of the 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 of ethanol preference and consumption.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399  80 GFYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLE 159
Cdd:cd19060     1 GYYLIQMYIPSLLIVILSWVSFWINMDAAPARVALGITTVLTMTTQSSGSRASLPKVSYVKAIDIWMAVCLLFVFSALLE 80

                          90       100
                  ....*....|....*....|....*....
gi 1831511399 160 YAAVGYISKRMKLVRARKESRMLTPLPHL 188
Cdd:cd19060    81 YAAVNFVSRQDRAKRIDTISRAAFPLAFL 109

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd19062     1 FYLLQLYIPSCMLVIVSWVSFWIDWTAVPGRVTLGVTTLLTMTTQSAGINAKLPPVSYIKAIDVWIGACVTFVFGALLEF 80

                          90       100
                  ....*....|....*....|....*...
gi 1831511399 161 AAVGYISKRMKlvRARKESRMLTPLPHL 188
Cdd:cd19062    81 AFVNYAGNRAK--RIDLISRILFPLLFL 106

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 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd19053     1 YFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIPYVKAIDMYLMGCFVFVFLALLEY 80

                  ....*.
gi 1831511399 161 AAVGYI 166
Cdd:cd19053    81 AFVNYI 86

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 1831511399  82 YIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEYA 161
Cdd:cd19055     2 YIIQSYMPSILLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSSLPRASAIKALDVYFWICYVFVFAALVEYA 81

                          90
                  ....*....|....
gi 1831511399 162 AVGYISKRMKLVRA 175
Cdd:cd19055    82 FAHYNADYRRPIDA 95

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVST--ESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd18990   105 MDLRKFPMDTQTCSLVFESYGYTTDDVVYKWKEGDTPVTilEKIELPQFDLTGVTTSEKTEVYPAGNYSRLTVTFTFKRR 184

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 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVS-YVKSIDIFLGVCFMMVFCSLLE 159
Cdd:cd19058     2 YFILETYVPSTLLVVLSWVSFWISLSSVPARTCIGVTTVLSMTTLMMGSRTSLPNANcFIKAIDVYLGICFSFIFGALLE 81

                          90       100
                  ....*....|....*....|....*.
gi 1831511399 160 YAAVGYISKRMKLVRARKESRMLTPL 185
Cdd:cd19058    82 YAVAHYCSLVQNPSNVDNYSRLLFPL 107

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 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATPARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd19057     1 FNAFQNYVPSSVTTMLSWVSFWIKKESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEF 80

                          90       100
                  ....*....|....*....|....*
gi 1831511399 161 AAVGYIskrMKLVRARKESRMLTPL 185
Cdd:cd19057    81 AVLNFL---IHVYRLDNYSRVIFPV 102

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVS-TESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd18993   105 MDLQYYPFDKQTCSIDLASYGYTTDDIVYLWKEEDPVQlPKGLSLPNFTLTNFKTGYCTSKTNTGEYSCLRVDFILRRE 183

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 1831511399  81 FYIIQIYLPSVLIVVISWVSFWLSRDATpARVALGVTTVLTMTTLMTMTNSSMPKVSYVKSIDIFLGVCFMMVFCSLLEY 160
Cdd:cd03559     1 YYAVSLLLPSILIMVVSWVGFWLPPDSG-ERVSFKITLLLTYSVFLIIVSDTLPATPYTPLIDVYFVVCMALLFIALLET 79

                  ....*.
gi 1831511399 161 AAVGYI 166
Cdd:cd03559    80 IFIVRL 85

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd03558   102 MDLKRFPFDQQNCTMKLESWTYDTTDIELVWDSERPDQADFLELPEWDIVEKRGRYCTVVYNTGIYSDITYRFRLKRQ 179

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSH--EKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd19040   103 MDLRRYPLDEQNCTLEIESYGYTTDDIEFYWNggEGAVTGVNKIELPQFSIIDYKMVSKKVEFTTGAYPRLSLSFRLKRN 182

extracellular domain of gamma-aminobutyric acid receptor subunit beta-3 (GABAAR-B3 or GABRB3); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-3 subunit, a protein that is encoded by the GABRB3 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-3 subunit forms heteropentamers with other GABAAR subunits, with alpha2-beta3-gamma2 and alpha3-beta3-gamma2 subtypes highly enriched in hippocampal pyramidal neurons and cholinergic neurons of the basal forebrain, respectively. Other heteromers include alpha1-beta3-gamma2 and alpha5-beta3-gamma2. GABRB3 mutations are likely associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism. GABRB3 might be associated with heroin dependence, and increased expression possibly contributing to the pathogenesis of heroin dependence. This gene may also be associated with the pathogenesis of other disorders such as Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, schizophrenia, and autism.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYV--SHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd19042   104 MDLRRYPLDEQNCTLEIESYGYTTDDIEFYwrGGDKAVTGVERIELPQFSIVEHRLVSRNVVFATGAYPRLSLSFRLKRN 183

extracellular domain of glycine receptor (GlyR); This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) of the amino acid neurotransmitter glycine. GlyR has four known isoforms of the alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands and a single beta-subunit (encoded by GLRB), all of which have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). Functional chloride-permeable GlyR ion channels are formed by 5 alpha subunit homopentamers or by alpha and beta subunit heteropentamers, which form complexes with either a 2alpha-3beta or 3alpha-2beta stoichiometry. The receptor can be activated by glycine as well as beta-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine is also a competitive antagonist of GlyR. In human, glycine receptor alpha1 and beta subunits are the major targets of mutations that cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions, leading to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli. Mutations in GlyR alpha2 are known to cause cortical neuronal migration/autism spectrum disorder and in GlyR alpha3 to cause inflammatory pain sensitization/rhythmic breathing.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVS-TESYELPQFVLQSIKVVNHTQKLS-SGEYSRLCWFFLFKRN 78
Cdd:cd18991   106 MDLHKYPLDTQTCPIQIESFGYTTENLIFKWNDDKPVQlNDGLELPQFELKGVSTSDCTKTYTeTGNFSCLEAKFHLQRN 185

extracellular domain of gamma-aminobutyric acid receptor subunit beta-2 (GABAAR-B2 or GABRB2); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-2 subunit, a protein that is encoded by the GABRB2 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-2 subunit forms heteropentamers with other GABAAR subunits, with alpha1-beta2-gamma2 subtype being the most prevalent isoform (approximately 50%-60% of all GABAARs), and are expressed in almost all regions of the brain. It also assembles less abundantly as alpha4beta2/3delta and alpha6beta2/3delta. Mutations or genetic variations of the genes encoding the GABRB2 and 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. GABRB2 plays important tumorigenic functions and acts as a novel oncogene in papillary thyroid carcinoma (PTC).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDI-MYVSHEKKSVS-TESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd19041   103 MDLRRYPLDEQNCTLEIESYGYTTDDIeFYWRGGDNAVTgVTKIELPQFSIVDYKLITKNVVFSTGSYPRLSLSFKLKRN 182

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIM-YVSHEKKSVS-TESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKRN 78
Cdd:cd19004   103 MDLTKYPMDKQTCTLQLESWGYNINDVMfYWTRGNDSVRgLDHLRLAQYTVEDYFTSVSEAVYETGNYPKLVFHFELKRN 182

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVS-TESYELPQFVLQSIKVVNH-TQKLSSGEYSRLCWFFLFKR 77
Cdd:cd19009   105 MDLKNFPMDVQTCIMQLESFGYTMNDLIFEWQEKGPVQvADGLTLPQFILKEEKDLRYcTKHYNTGKFTCIEVRFHLER 183

extracellular domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family contains extracellular domain (ECD) of bacterial pentameric ligand-gated ion channels (pLGICs), including ones from Gloebacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC). These prokaryotic homologs of Cys-loop receptors have been useful in understanding their eukaryotic counterparts. The largely beta-sheet ECD in this family is similar to other pLGICs, but lacks the cysteine loop and an intracellular domain. While most pLGICs undergo desensitization on prolonged exposure to the agonist, GLIC is activated by protons, but does not desensitize, even at proton concentrations eliciting maximal electrophysiological response (pH 4.5). Studies show that GLIC activation is inhibited by most general anaesthetics at clinical concentrations, including xenon which has been used in clinical practice as a potent gaseous anesthetic for decades. Xenon binding sites have been identified in three distinct regions of the TMD: in a large intra-subunit cavity, in the pore, and at the interface between adjacent subunits.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSG--EYSRL 69
Cdd:cd18988   103 MDLRRFPFDRQTLTIELESFSYDPDEVVLVVDQDDTGLSDDLSLPEWSIGDVSAEVSSYKGSNGgeEFSRF 173

extracellular domain of gamma-aminobutyric acid receptor subunit rho-3 (GABAA-rho3); This family contains extracellular domain (ECD) of the rho subunit 3 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR3 gene which maps to a different chromosome to that of GABRR1 and GABRR2. While close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event, GABRR3 may have arisen by duplication of a GABRR1/GABRR2 progenitor. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, some individuals contain a variant that is predicted to inactivate this gene product.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIM-YVSHEKKSVSTESY-ELPQFVLQSIKVVNHTQKLSS-GEYSRLCWFFLFKR 77
Cdd:cd19048   105 MDFSRFPLDTQNCSLELESYAYNEDDLMlYWKHGNESLSTDEHiSLSQFFIEEFSASSGLAFYSStGWYNRLFINFALRR 184

                  ..
gi 1831511399  78 NI 79
Cdd:cd19048   185 HI 186

extracellular domain of gamma-aminobutyric acid receptor subunit rho-2 (GABA-rho2 or GABRR2); This family contains extracellular domain (ECD) of the rho subunit 2 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR2 gene which exists next to GABRR1 (encoding rho subunit 1) on the chromosome region thought to be associated with susceptibility for psychiatric disorders and epilepsy. Close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event. Rho1 is expressed in many areas of the brain, but especially high in the retina. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, mutations in the GABRR2 gene may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR2 is also associated with susceptibility to bipolar schizoaffective disorder, as well as alcohol dependence and general cognitive ability. GABA-rho2 receptors expressed pre-synaptically in the spinal dorsal horn have been implicated in pain perception and identified as a novel target for analgesia.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIM-YVSHEKKSVST-ESYELPQFVLQSIKVVNHTQKLSS-GEYSRLCWFFLFKR 77
Cdd:cd19047   105 MDFSRFPLDSQTCSLELESYAYTDEDLMlYWKNGNESLKTdEKISLSQFLIQKFHTTSRLAFYSStGWYNRLYINFTLRR 184

                  ..
gi 1831511399  78 NI 79
Cdd:cd19047   185 HI 186

extracellular domain of gamma-aminobutyric acid receptor subunit rho-1 (GABA-rho1 or GABRR1); This family contains extracellular domain (ECD) of the rho subunit 1 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR1 gene, expressed in many areas of the brain, but especially high in the retina. GABRR1 exists next to GABRR2 (encoding rho subunit 2) on the chromosome region thought to be associated with susceptibility for psychiatric disorders and epilepsy. Close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, mutations in the GABRR1 gene may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder, and may be associated with alcohol dependency.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIM-YVSHEKKSVST-ESYELPQFVLQSIKVVNHTQKLSS-GEYSRLCWFFLFKR 77
Cdd:cd19046   105 MDFSRFPLDTQTCSLEIESYAYTEDDLMlYWKNGNDSLKTdERISLSQFLIQEFHTTTKLAFYSStGWYNRLYINFTLRR 184

                  ..
gi 1831511399  78 NI 79
Cdd:cd19046   185 HI 186

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYV----SHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFK 76
Cdd:cd19036   119 MHLEDFPMDVHACPLKFGSYAYTKTEVVYSwtlgKNKSVEVAPDGSRLNQYDLLGHVVGTETIRSSTGEYVVMTTHFHLK 198

                  .
gi 1831511399  77 R 77
Cdd:cd19036   199 R 199

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYV----SHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFK 76
Cdd:cd19038   118 MQLEDFPMDAHACPLKFGSYAYPNSEVVYVwtngTTKSVVVAEDGSRLNQYHLMGQTVGTENISTSTGEYTIMTAHFHLK 197

                  .
gi 1831511399  77 R 77
Cdd:cd19038   198 R 198

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6 or GABRA6); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6), a protein that is encoded by the GABRA6 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-6 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha6-beta-gamma2 found extrasynaptically, alpha6-beta2/3-delta in the cerebellar granule cells and likely also forms alpha1-alpha6-beta-gamma/alpha1-alpha6-beta-delta. A GABRA6 mutation from Arg to Trp, has been identified as a susceptibility gene that may contribute to the pathogenesis of childhood absence epilepsy and cause neuronal disinhibition and increase in seizures via a reduction of alphabetagamma and alphabetadelta receptor function and expression. Polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress. Alpha6-containing receptors lack high sensitivity to diazepam.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYVSHE----KKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFK 76
Cdd:cd19039   117 MRLVNFPMDGHACPLKFGSYAYPKSEIVYTWKKgplySVEVPEESSSLLQYDLIGQTVSSETLKSNTGEYVVMTVYFHLQ 196

                  .
gi 1831511399  77 R 77
Cdd:cd19039   197 R 197

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4 or GABRA4); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4), a protein that is encoded by the GABRA4 gene in humans, with biased expression in the brain and heart. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-4 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha2alpha4beta1gamma1, all four subunits existing on the same gene cluster. Alpha-4 is involved in the etiology of autism and eventually increases autism risk through interaction with the beta-1 (GABRB1) subunit. Polymorphism in GABRA4 may trigger migraine by ethanol, while another is associated to faster reaction times and with lower ethanol effects. A rare variant in GABRA4 may have modest physiological effect in autism spectrum disorder etiology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYV----SHEKKSVSTESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFK 76
Cdd:cd19037   118 MRLVDFPMDGHACPLKFGSYAYPKSEMIYTwtkgPEKSVEVPPESSSLVQYDLIGQTVSSETIKSITGEYIVMTVYFHLR 197

                  .
gi 1831511399  77 R 77
Cdd:cd19037   198 R 198

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 1831511399   1 MDLKLFPMDSQHCKLEIESYGYSILDIMYvSHEKKSVST---ESYELPQFVLQSIKVVNHTQKLSSGEYSRLCWFFLFKR 77
Cdd:cd19045   103 LQLHNFPMDEHSCPLIFSSYGYPKEEMIY-RWRKNSVEAadqKSWRLYQFDFMGLRNTTEIVTTSAGDYVVMTIYFELSR 181