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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   1 MTLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19005   25 MTLYLRHYWKDERLSFPSTANKSMTFDGRLVKKIWVPDVFFVHSKRSFIHDTTTDNIMLRVFPDGHVLYSLRITVTAMCN 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19005  105 MDFSRFPLDTQTCSLELESYAYTEDDLMLYWKNGNESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 184

                 ..
gi 767942558 161 HI 162
Cdd:cd19005  185 HI 186

extracellular domain of gamma-aminobutyric acid receptor subunit rho; This family contains extracellular domain of rho subunits (rho1, rho2, and rho3, encoded by GABRR1, GABRR2, and GABRR3, respectively) of type-A gamma-aminobutyric acid receptor (GABAAR). These subunits homo-oligomerize to form GABAA-rho receptors (formerly classified as GABA-rho or GABAC receptor), but do not co-assemble with any of the classical GABAA subunits. They are especially high expression in the retina and their distinctive pharmacological properties are unique; they are not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids. In humans, mutations in the GABRR1 and GABRR2 genes may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder while a SNP in GABRR2 has been reported to show association with autism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   1 MTLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19005   25 MTLYLRHYWKDERLSFPSTANKSMTFDGRLVKKIWVPDVFFVHSKRSFIHDTTTDNIMLRVFPDGHVLYSLRITVTAMCN 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19005  105 MDFSRFPLDTQTCSLELESYAYTEDDLMLYWKNGNESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 184

                 ..
gi 767942558 161 HI 162
Cdd:cd19005  185 HI 186

transmembrane domain of rho subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the rho subunit of type-A gamma-aminobutyric acid receptor (GABAAR), which includes rho1-3. 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. These rho subunits homo-oligomerize to form GABAA-rho receptors (formerly classified as GABA-rho or GABAC receptor) but do not co-assemble with any of the classical GABAA subunits. They are especially high expression in the retina and their distinctive pharmacological properties are unique; they are not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids. In humans, mutations in the rho-1 and rho genes, GABRR1 and GABRR2, may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder while a SNP in GABRR2 has been reported to show association with autism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558 163 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLE 242
Cdd:cd19059    1 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMSTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558 243 YAAVNYLttvqerkerklrekfpcmcgmlhsktmmldgsyseseanslagyprshilteeerqdkivvhlglsgeanaar 322
Cdd:cd19059   81 YAAVNYL------------------------------------------------------------------------- 87

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 767942558 323 kkgllkgqtgfrifqNTHAIDKYSRLIFPASYIFFNLIYWS 363
Cdd:cd19059   88 ---------------NTHAIDKYSRIIFPGAYILFNLIYWS 113

Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558    1 MTLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHsKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:pfam02931  49 TNVWLRQTWTDPRLAWNPEDYGGITSLRLPSDKIWKPDIVLYN-KADGIHEVTTPNTNVRVYYDGTVLWSPPAIYKSSCS 127

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDeSLKTDEKISLSQFLIQKFHTTSRLAF---YSSTGWYNRLY---- 153
Cdd:pfam02931 128 IDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDDDP-PVVELEEIDLSDFWLNGEWDIVDVPAkrrEYPYGCYSELTgdvt 206

                  ....*....
gi 767942558  154 INFTLRRHI 162
Cdd:pfam02931 207 FYFTLRRKP 215

extracellular domain of gamma-aminobutyric acid receptor subunit rho; This family contains extracellular domain of rho subunits (rho1, rho2, and rho3, encoded by GABRR1, GABRR2, and GABRR3, respectively) of type-A gamma-aminobutyric acid receptor (GABAAR). These subunits homo-oligomerize to form GABAA-rho receptors (formerly classified as GABA-rho or GABAC receptor), but do not co-assemble with any of the classical GABAA subunits. They are especially high expression in the retina and their distinctive pharmacological properties are unique; they are not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids. In humans, mutations in the GABRR1 and GABRR2 genes may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder while a SNP in GABRR2 has been reported to show association with autism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   1 MTLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19005   25 MTLYLRHYWKDERLSFPSTANKSMTFDGRLVKKIWVPDVFFVHSKRSFIHDTTTDNIMLRVFPDGHVLYSLRITVTAMCN 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19005  105 MDFSRFPLDTQTCSLELESYAYTEDDLMLYWKNGNESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 184

                 ..
gi 767942558 161 HI 162
Cdd:cd19005  185 HI 186

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 767942558    2 TLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCNM 81
Cdd:TIGR00860  79 NIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDARFHGITMTNVLVRIHPNGSVLYSPRITLTLACPM 158

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   82 DFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDEsLKTDEK--ISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLR 159
Cdd:TIGR00860 159 DLRNFPFDVQNCSLKFESWGYTTNDIKLEWKEQGA-VQVDDSlfISLPEFELLGVYGTRYCTSETNTGEYPCLTFSFVLR 237

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  160 RHIFFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLS 239
Cdd:TIGR00860 238 RRPLYYLLQLYIPSILIVILSWVSFWLPADASGARVSLGITTLLTMTTFSSGVRESLPAVSYVKAIDVYFAVCMAFVFLA 317

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  240 VLEYAAVNYL----------TTVQERKERKLREKFPcmcGMLHSKTMMLDGSYSESEANSLAGYPRSHILTEEER----Q 305
Cdd:TIGR00860 318 LLETAFVNYVhhkdpaqgkrHLLLERCAWRLCKQEP---GEDYRRPALDHASLSSVEMRAKDGGRGLESPTERQRllhsP 394

                         330       340       350       360       370       380
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767942558  306 DKIVVHLGLSGEANAARKKGLLKGQTGFRIFQNTH-----AIDKYSRLIFPASYIFFNLIYWSVF 365
Cdd:TIGR00860 395 PPAEGDLDLAGILEEVRIAHRFRKRDESEEVVRDWkfrakVIDKLSRMAFPLAFLLFNIGYWMSY 459

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 767942558   1 MTLYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19048   25 MTLYLRHYWKDERLSFPSTKNKSMTFDGRLIKKIWVPDVFFVHSKRSFIHDTTMENVMLRVYPDGNVLFSLRITVSAMCF 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19048  105 MDFSRFPLDTQNCSLELESYAYNEDDLMLYWKHGNESLSTDEHISLSQFFIEEFSASSGLAFYSSTGWYNRLFINFALRR 184

                 ..
gi 767942558 161 HI 162
Cdd:cd19048  185 HI 186

transmembrane domain of rho subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the rho subunit of type-A gamma-aminobutyric acid receptor (GABAAR), which includes rho1-3. 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. These rho subunits homo-oligomerize to form GABAA-rho receptors (formerly classified as GABA-rho or GABAC receptor) but do not co-assemble with any of the classical GABAA subunits. They are especially high expression in the retina and their distinctive pharmacological properties are unique; they are not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids. In humans, mutations in the rho-1 and rho genes, GABRR1 and GABRR2, may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder while a SNP in GABRR2 has been reported to show association with autism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558 163 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLE 242
Cdd:cd19059    1 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMSTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558 243 YAAVNYLttvqerkerklrekfpcmcgmlhsktmmldgsyseseanslagyprshilteeerqdkivvhlglsgeanaar 322
Cdd:cd19059   81 YAAVNYL------------------------------------------------------------------------- 87

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 767942558 323 kkgllkgqtgfrifqNTHAIDKYSRLIFPASYIFFNLIYWS 363
Cdd:cd19059   88 ---------------NTHAIDKYSRIIFPGAYILFNLIYWS 113

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 767942558   2 TLYLRHYWKDERLAFSSasNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCNM 81
Cdd:cd19004   26 TIFLRQRWTDERLCFEG--NKSLSLDGRLVELLWVPDTFIVDSKKSFLHDITVENRLIRIFPNGTVLYALRITTTVACSM 103

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767942558  82 DFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYsSTGWYNRLYINFTLRR 160
Cdd:cd19004  104 DLTKYPMDKQTCTLQLESWGYNINDVMFYWTRGNDSVRGLDHLRLAQYTVEDYFTSVSEAVY-ETGNYPKLVFHFELKR 181

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 767942558 164 FFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLEY 243
Cdd:cd19049    1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                         90       100
                 ....*....|....*....|..
gi 767942558 244 AAVNYLTTvqERKERKLREKFP 265
Cdd:cd19049   81 AVVNYLKA--SKIDRISRILFP 100

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 767942558   1 MTLYLRHYWKDERLAFSSaSNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19001   25 MTVFLHQSWRDERLSYNH-TNETLGLDSRFVDKLWLPDTFIVNAKSAWFHDVTVENKLIRLQPDGVILYSSRITSTVACD 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19001  104 MDLTKYPMDEQECMLDLESYGYSSEDIVYHWSENQEHIHGLDKLELAQFTITNYRFTTEMMNFKSAGQFPRLSLHFHLRR 183

                 .
gi 767942558 161 H 161
Cdd:cd19001  184 N 184

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 767942558   1 MTLYLRHYWKDERLAFSSASnKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd18999   24 LTMYFQQSWRDKRLAYNGIP-LNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACM 102

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYsSTGWYNRLYINFTLRR 160
Cdd:cd18999  103 MDLRRYPLDEQNCTLEIESYGYTTDDIEFYWQGGDNAVTGVEKIELPQFSIVEYRLVSREVVF-TTGSYPRLSLSFRLKR 181

                 .
gi 767942558 161 H 161
Cdd:cd18999  182 N 182

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 767942558   1 MTLYLRHYWKDERLAFSSASnKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19040   24 LTMYFQQSWRDKRLSYSGIP-LNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACM 102

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYsSTGWYNRLYINFTLRR 160
Cdd:cd19040  103 MDLRRYPLDEQNCTLEIESYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIIDYKMVSKKVEF-TTGAYPRLSLSFRLKR 181

                 .
gi 767942558 161 H 161
Cdd:cd19040  182 N 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 767942558   1 MTLYLRHYWKDERLAFSSASnKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd19042   25 LTMYFQQYWRDKRLAYSGIP-LNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACM 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRLAFYsSTGWYNRLYINFTLRR 160
Cdd:cd19042  104 MDLRRYPLDEQNCTLEIESYGYTTDDIEFYWRGGDKAVTGVERIELPQFSIVEHRLVSRNVVF-ATGAYPRLSLSFRLKR 182

                 .
gi 767942558 161 H 161
Cdd:cd19042  183 N 183

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 767942558   3 LYLRHYWKDERLAFSSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCNMD 82
Cdd:cd18993   27 LTFRQEWYDPRLRYDDTGGKPEYLTLTDDSKIWKPDTFFQNEKEGHFHNIDKPNVYLRIYPDGKVLYSVRISLTLSCPMD 106

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  83 FSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDeSLKTDEKISLSQFLIQKFHT---TSRlafySSTGWYNRLYINFTLR 159
Cdd:cd18993  107 LQYYPFDKQTCSIDLASYGYTTDDIVYLWKEED-PVQLPKGLSLPNFTLTNFKTgycTSK----TNTGEYSCLRVDFILR 181

                 ..
gi 767942558 160 RH 161
Cdd:cd18993  182 RE 183

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 767942558   3 LYLRHYWKDERLAF-SSASNKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCNM 81
Cdd:cd19008   26 FYFRQFWTDPRLAFkKSPGVESLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSNEFLRIHHSGSITRSIRLTITASCPM 105

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767942558  82 DFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKTDEKISLSQFLIQKFHTTSRlAFYSSTGWYNRLYINFTLRR 160
Cdd:cd19008  106 NLQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGPNSVGISPEVELPQFKVLGHRQRAR-EISLTTGNYSRLACEIQFVR 183

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 767942558 164 FFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLEY 243
Cdd:cd19062    1 FYLLQLYIPSCMLVIVSWVSFWIDWTAVPGRVTLGVTTLLTMTTQSAGINAKLPPVSYIKAIDVWIGACVTFVFGALLEF 80

                         90       100
                 ....*....|....*....|..
gi 767942558 244 AAVNYLTTVQERKERKLREKFP 265
Cdd:cd19062   81 AFVNYAGNRAKRIDLISRILFP 102

extracellular domain of glycine receptor beta subunit; This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) beta subunit of the amino acid neurotransmitter glycine encoded by GLRB gene. These subunits form heteropentamers with a combination of alpha and beta subunits, either a 2alpha-3beta or 3alpha-2beta stoichiometry. While the alpha subunits contain binding sites for agonists and antagonists and are responsible for ion channel formation, the beta subunit displays structural and regulatory functions, such as GlyR clustering in synaptic locations by interaction between intracellular loop domains with the scaffolding protein gephyrin, and control of pharmacologic responses to agonist or allosteric modulators due in part to the presence of interfaces alpha/beta and beta/beta. GLRB gene mutations are associated with the neurological disorder hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli, as well as agoraphobic cognitions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558   1 MTLYLRHYWKDERLAFSSASNKS--MTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAM 78
Cdd:cd19010   25 VNIFLRQKWNDPRLKLPNDFRGSdaLTVDPTMFKCLWKPDLFFANEKSANFHDVTQENILLFIFRDGDVLVSMRLSITLS 104

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  79 CNMDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESlkTDEKISLSQFLIQK--FHTTSRLAFYSSTGWYNRLYINF 156
Cdd:cd19010  105 CPLDLTLFPMDTQRCKMQLESFGYTTDDLRFIWQSGDPV--QLEKIALPQFDIKKedIEYGNCTKYYKGTGYYTCVEVIF 182

                 ....*
gi 767942558 157 TLRRH 161
Cdd:cd19010  183 TLRRQ 187

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 767942558   1 MTLYLRHYWKDERLAFSSASnKSMTFDGRLVKKIWVPDVFFVHSKRSFTHDTTTDNIMLRVFPDGHVLYSMRITVTAMCN 80
Cdd:cd18998   24 IDVFFRQTWKDERLKFKGPM-KILRLNNLMASKIWTPDTFFHNGKKSVAHNMTTPNKLLRIQDDGTLLYTMRLTIHAECP 102

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767942558  81 MDFSHFPLDSQTCSLELESYAYTDEDLMLYWKNGDESLKT--DEKISLSQFLIQKfHTTSRLAFYSSTGWYNRLYINFTL 158
Cdd:cd18998  103 MHLEDFPMDAHSCPLKFGSYAYPKSEVVYTWTYGPKKSVEvaEDGSRLNQYDLIG-QTVGSETIKSSTGEYVVMTVHFHL 181

                 ..
gi 767942558 159 RR 160
Cdd:cd18998  182 KR 183

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 767942558 164 FFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLEY 243
Cdd:cd19053    1 YFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIPYVKAIDMYLMGCFVFVFLALLEY 80

                 ....*.
gi 767942558 244 AAVNYL 249
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 767942558 165 FLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMTTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLEYA 244
Cdd:cd19055    2 YIIQSYMPSILLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSSLPRASAIKALDVYFWICYVFVFAALVEYA 81