extracellular domain of gamma-aminobutyric acid receptor subunit beta (GABAAR-B or GABRB); This family contains extracellular domain (ECD) of beta subunits of type-A gamma-aminobutyric acid receptor (GABAAR), which include beta1-beta4 in vertebrates. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to 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 LBD. The channels must 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. 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. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd18999    26 MYFQQSWRDKRLAYNGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 105

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd18999   106 RRYPLDEQNCTLEIESYGYTTDDIEFYWQGGDNAVTGVEKIELPQFSIVEYRLVSREVVFTTGSYPRLSLSFRLKRN 182

extracellular domain of gamma-aminobutyric acid receptor subunit beta (GABAAR-B or GABRB); This family contains extracellular domain (ECD) of beta subunits of type-A gamma-aminobutyric acid receptor (GABAAR), which include beta1-beta4 in vertebrates. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to 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 LBD. The channels must 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. 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. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd18999    26 MYFQQSWRDKRLAYNGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 105

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd18999   106 RRYPLDEQNCTLEIESYGYTTDDIEFYWQGGDNAVTGVEKIELPQFSIVEYRLVSREVVFTTGSYPRLSLSFRLKRN 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 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd19042    27 MYFQQYWRDKRLAYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd19042   107 RRYPLDEQNCTLEIESYGYTTDDIEFYWRGGDKAVTGVERIELPQFSIVEHRLVSRNVVFATGAYPRLSLSFRLKRN 183

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 1953290593   1 MYFQQSWKDKRLSYSGIPL--NLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMM 78
Cdd:cd18990    26 IYFRQYWRDPRLAFDHNGCnkNLTLSGEMLSKIWTPDTFFVNSKKAKFHDVTTPNILLRIYPNGTVLYSYRLTVTAPCSM 105

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1953290593  79 DLRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd18990   106 DLRKFPMDTQTCSLVFESYGYTTDDVVYKWKEGDTPVTILEKIELPQFDLTGVTTSEKTEVYPAGNYSRLTVTFTFKRR 184

extracellular domain of gamma-aminobutyric acid receptor subunit theta (GABRQ); This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR), and encoded by the GABRQ gene, which is mapped to chromosome Xq28 in a cluster of genes that also that encode the alpha 3 and epsilon subunits. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAAR theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd19003    27 MFFHQTWKDSRLAYYETTLNLTLDYRMHEKLWVPDCYFLNSKDAFVHDVTVENRVFQLHPDGTVRYGIRLTTTAACSLDL 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKR 156
Cdd:cd19003   107 HKFPMDKQACKLEVESYGYTVEDIILFWEDNGNAIHMTEELHIPQFTFLGRTITSKEVYFYTGSYIRLILKFQVQR 182

extracellular domain of gamma-aminobutyric acid receptor subunit delta; This family contains extracellular domain of delta 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 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. 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 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd19001    27 VFLHQSWRDERLSYNHTNETLGLDSRFVDKLWLPDTFIVNAKSAWFHDVTVENKLIRLQPDGVILYSSRITSTVACDMDL 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEF-TTGAYPRLSLSFRLKRN 157
Cdd:cd19001   107 TKYPMDEQECMLDLESYGYSSEDIVYHWSENQEHIHGLDKLELAQFTITNYRFTTEMMNFkSAGQFPRLSLHFHLRRN 184

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 1953290593   1 MYFQQSWKDKRLSYSGIPlNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd19004    27 IFLRQRWTDERLCFEGNK-SLSLDGRLVELLWVPDTFIVDSKKSFLHDITVENRLIRIFPNGTVLYALRITTTVACSMDL 105

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd19004   106 TKYPMDKQTCTLQLESWGYNINDVMFYWTRGNDSVRGLDHLRLAQYTVEDYFTSVSEAVYETGNYPKLVFHFELKRN 182

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 1953290593 160 YFILQTYMPSTLITILSWVSFWINYDASAARVALGITTVLTMTTISTHLRETLPKIPYVKAIDIYLMGCFVFVFLALLEY 239
Cdd:cd19053     1 YFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIPYVKAIDMYLMGCFVFVFLALLEY 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593 240 AFVNYIffgkgpqkkgaskqdqsaneknklemnkvqvdahgnillsalelrteasgsevltgasepqaagvfafdsasvq 319
Cdd:cd19053    81 AFVNYI-------------------------------------------------------------------------- 86

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1953290593 320 frrplssrdaygrapdrlgahgkgrirrrasqlkvkipdltDVNSIDKWSRMFFPITFSLFNVVYW 385
Cdd:cd19053    87 -----------------------------------------DVNAIDRWSRIIFPITFSFFNLVYW 111

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 1953290593   2 YFQQSWKDKRLSYSGIPL--NLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMD 79
Cdd:cd19008    27 YFRQFWTDPRLAFKKSPGveSLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSNEFLRIHHSGSITRSIRLTITASCPMN 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1953290593  80 LRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd19008   107 LQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGPNSVGISPEVELPQFKVLGHRQRAREISLTTGNYSRLACEIQFVRS 184

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 1953290593 160 YFILQTYMPSTLITILSWVSFWINYDASAARVALGITTVLTMTTISTHLRETLPKIPYVKAIDIYLMGCFVFVFLALLEY 239
Cdd:cd19049     1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                  ....*..
gi 1953290593 240 AFVNYIF 246
Cdd:cd19049    81 AVVNYLK 87

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593   1 MYFQQSWKDKRLSYSGIP-----LNLTLDNRVadqlWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAA 75
Cdd:cd18993    27 LTFRQEWYDPRLRYDDTGgkpeyLTLTDDSKI----WKPDTFFQNEKEGHFHNIDKPNVYLRIYPDGKVLYSVRISLTLS 102

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593  76 CMMDLRRYPLDEQNCTLEIESYGYTTDDIEFYWNgGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLK 155
Cdd:cd18993   103 CPMDLQYYPFDKQTCSIDLASYGYTTDDIVYLWK-EEDPVQLPKGLSLPNFTLTNFKTGYCTSKTNTGEYSCLRVDFILR 181

                  ..
gi 1953290593 156 RN 157
Cdd:cd18993   182 RE 183

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 1953290593   1 MYFQQSWKDKRLSY-SGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMD 79
Cdd:cd19046    27 LYLRHYWKDERLSFpSTNNQSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNVMLRVQPDGKVLYSLRVTVTAMCNMD 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593  80 LRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEF-TTGAYPRLSLSFRLKRNI 158
Cdd:cd19046   107 FSRFPLDTQTCSLEIESYAYTEDDLMLYWKNGNDSLKTDERISLSQFLIQEFHTTTKLAFYsSTGWYNRLYINFTLRRHI 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 1953290593   1 MYFQQSWKDKRLSYSGIP-LNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMD 79
Cdd:cd19047    27 LYLRHYWKDERLSFPSTTnKSMTFDGRLVKKIWVPDVFFVHSKRSFIHDTTTDNIMLRVFPDGHVLYSMRITVTAMCNMD 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953290593  80 LRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEF-TTGAYPRLSLSFRLKRNI 158
Cdd:cd19047   107 FSRFPLDSQTCSLELESYAYTDEDLMLYWKNGNESLKTDEKISLSQFLIQKFHTTSRLAFYsSTGWYNRLYINFTLRRHI 186

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 1953290593   2 YFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDLR 81
Cdd:cd18998    27 FFRQTWKDERLKFKGPMKILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKLLRIQDDGTLLYTMRLTIHAECPMHLE 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1953290593  82 RYPLDEQNCTLEIESYGYTTDDIEFYWNGG--EGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKRN 157
Cdd:cd18998   107 DFPMDAHSCPLKFGSYAYPKSEVVYTWTYGpkKSVEVAEDGSRLNQYDLIGQTVGSETIKSSTGEYVVMTVHFHLKRK 184

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 1953290593 160 YFILQTYMPSTLITILSWVSFWINYDaSAARVALGITTVLTMTTISTHLRETLPKIPYVKAIDIYLMGCFVFVFLALLEY 239
Cdd:cd03559     1 YYAVSLLLPSILIMVVSWVGFWLPPD-SGERVSFKITLLLTYSVFLIIVSDTLPATPYTPLIDVYFVVCMALLFIALLET 79

                  ....*...
gi 1953290593 240 AFVNYIFF 247
Cdd:cd03559    80 IFIVRLVH 87

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 1953290593   1 MYFQQSWKDKRLSYSGiPLN-LTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMD 79
Cdd:cd19035    45 VFFRQRWKDERLKFKG-PMNiLRLNNLMASKIWTPDTFFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMH 123

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1953290593  80 LRRYPLDEQNCTLEIESYGYTTDDIEFYW--NGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKR 156
Cdd:cd19035   124 LEDFPMDAHSCPLKFGSYAYTTSEVTYIWtyNASDSVQVAPDGSRLNQYDLLGQTIGKETIKSSTGEYTVMTAHFHLKR 202

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 1953290593   1 MYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDL 80
Cdd:cd19034    36 VFFRQSWKDERLKFKGPMTVLRLNNLMASKIWTPDTFFHNGKKSVAHNMTMPNKLLRITEDGTLLYTMRLTVRAECPMHL 115

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1953290593  81 RRYPLDEQNCTLEIESYGYTTDDIEFYWNGG--EGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLKR 156
Cdd:cd19034   116 EDFPMDAHACPLKFGSYAYTRAEVVYEWTREpaRSVVVAEDGSRLNQYDLLGQTVDSGIVQSSTGEYVVMTTHFHLKR 193

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 1953290593 160 YFILQTYMPSTLITILSWVSFWINYDASAARVALGITTVLTMTTISTHLRETLPKIPYVKAIDIYLMGCFVFVFLALLEY 239
Cdd:cd19054     1 YFTIQTYIPCILTVVLSWVSFWINKDAVPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFAALMEY 80

                  ....*
gi 1953290593 240 AFVNY 244
Cdd:cd19054    81 GTLHY 85