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 375493572    2 RPGFGGPAIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFI 81
Cdd:TIGR00860  47 RPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDARF 126

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572   82 HDTTTDNVMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNdSLKTDE--RISLS 159
Cdd:TIGR00860 127 HGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKLEWKEQG-AVQVDDslFISLP 205

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  160 QFLIQEFHTTTKLAFYSSTGWYNRLYINFTLRRHIFFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVPLGITTVLTMST 239
Cdd:TIGR00860 206 EFELLGVYGTRYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADASGARVSLGITTLLTMTT 285

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  240 IITGVNASMPRVSYIKAVDIYLWVSFVFVFLSVLEYAAVNYL----------TTVQERKEQKLREKLPCTSGLPP----- 304
Cdd:TIGR00860 286 FSSGVRESLPAVSYVKAIDVYFAVCMAFVFLALLETAFVNYVhhkdpaqgkrHLLLERCAWRLCKQEPGEDYRRPaldha 365

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  305 PRTAMLDGNYSDGEVNDL---DNYMPENGEKPDRMMVQLTLASERSSPQRKSQRSSYVSMRID----THAIDKYSRIIFP 377
Cdd:TIGR00860 366 SLSSVEMRAKDGGRGLESpteRQRLLHSPPPAEGDLDLAGILEEVRIAHRFRKRDESEEVVRDwkfrAKVIDKLSRMAFP 445

                         410
                  ....*....|....
gi 375493572  378 AAYILFNLIYWSIF 391
Cdd:TIGR00860 446 LAFLLFNIGYWMSY 459

Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572    2 RPGFGGPAIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFI 81
Cdd:TIGR00860  47 RPVFGGPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGVTLVRTPDDSIWVPDIFFYNEKDARF 126

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572   82 HDTTTDNVMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNdSLKTDE--RISLS 159
Cdd:TIGR00860 127 HGITMTNVLVRIHPNGSVLYSPRITLTLACPMDLRNFPFDVQNCSLKFESWGYTTNDIKLEWKEQG-AVQVDDslFISLP 205

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  160 QFLIQEFHTTTKLAFYSSTGWYNRLYINFTLRRHIFFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVPLGITTVLTMST 239
Cdd:TIGR00860 206 EFELLGVYGTRYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADASGARVSLGITTLLTMTT 285

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  240 IITGVNASMPRVSYIKAVDIYLWVSFVFVFLSVLEYAAVNYL----------TTVQERKEQKLREKLPCTSGLPP----- 304
Cdd:TIGR00860 286 FSSGVRESLPAVSYVKAIDVYFAVCMAFVFLALLETAFVNYVhhkdpaqgkrHLLLERCAWRLCKQEPGEDYRRPaldha 365

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  305 PRTAMLDGNYSDGEVNDL---DNYMPENGEKPDRMMVQLTLASERSSPQRKSQRSSYVSMRID----THAIDKYSRIIFP 377
Cdd:TIGR00860 366 SLSSVEMRAKDGGRGLESpteRQRLLHSPPPAEGDLDLAGILEEVRIAHRFRKRDESEEVVRDwkfrAKVIDKLSRMAFP 445

                         410
                  ....*....|....
gi 375493572  378 AAYILFNLIYWSIF 391
Cdd:TIGR00860 446 LAFLLFNIGYWMSY 459

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 375493572 195 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVPLGITTVLTMSTIITGVNASMPRVSYIKAVDIYLWVSFVFVFLSVLE 274
Cdd:cd19059    1 FFFLLQTYFPATLMVMLSWVSFWIDRRAVPARVSLGITTVLTMSTIITGVNASMPRVSYVKAVDIYLWVSFVFVFLSVLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572 275 YAAVNYLttvqerkeqklreklpctsglppprtamldgnysdgevndldnympengekpdrmmvqltlasersspqrksq 354
Cdd:cd19059   81 YAAVNYL------------------------------------------------------------------------- 87

                        170       180       190
                 ....*....|....*....|....*....|....*
gi 375493572 355 rssyvsmriDTHAIDKYSRIIFPAAYILFNLIYWS 389
Cdd:cd19059   88 ---------NTHAIDKYSRIIFPGAYILFNLIYWS 113

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 375493572   9 AIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDN 88
Cdd:cd19046    1 AIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNQSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  89 VMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHT 168
Cdd:cd19046   81 VMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKNGNDSLKTDERISLSQFLIQEFHT 160

                        170       180
                 ....*....|....*....|....*.
gi 375493572 169 TTKLAFYSSTGWYNRLYINFTLRRHI 194
Cdd:cd19046  161 TTKLAFYSSTGWYNRLYINFTLRRHI 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 375493572   9 AIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDN 88
Cdd:cd19047    1 AIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTTNKSMTFDGRLVKKIWVPDVFFVHSKRSFIHDTTTDN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  89 VMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHT 168
Cdd:cd19047   81 IMLRVFPDGHVLYSMRITVTAMCNMDFSRFPLDSQTCSLELESYAYTDEDLMLYWKNGNESLKTDEKISLSQFLIQKFHT 160

                        170       180
                 ....*....|....*....|....*.
gi 375493572 169 TTKLAFYSSTGWYNRLYINFTLRRHI 194
Cdd:cd19047  161 TSRLAFYSSTGWYNRLYINFTLRRHI 186

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 375493572  12 VGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTN-NLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNVM 90
Cdd:cd18990    3 VTVEIWVQSIGSISEINMDFTLDIYFRQYWRDPRLAFDHNGcNKNLTLSGEMLSKIWTPDTFFVNSKKAKFHDVTTPNIL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  91 LRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHTTT 170
Cdd:cd18990   83 LRIYPNGTVLYSYRLTVTAPCSMDLRKFPMDTQTCSLVFESYGYTTDDVVYKWKEGDTPVTILEKIELPQFDLTGVTTSE 162

                        170       180
                 ....*....|....*....|...
gi 375493572 171 KLAFYsSTGWYNRLYINFTLRRH 193
Cdd:cd18990  163 KTEVY-PAGNYSRLTVTFTFKRR 184

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 375493572    1 MRPG-FGGPAIPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHsKRS 79
Cdd:pfam02931  16 VRPVaNGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSDKIWKPDIVLYN-KAD 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572   80 FIHDTTTDNVMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDErISLS 159
Cdd:pfam02931  95 GIHEVTTPNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDDDPPVVELEE-IDLS 173

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 375493572  160 QFLIQEFHTTTKLAF---YSSTGWYNRLY----INFTLRRHI 194
Cdd:pfam02931 174 DFWLNGEWDIVDVPAkrrEYPYGCYSELTgdvtFYFTLRRKP 215

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 375493572  10 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFpSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNV 89
Cdd:cd18999    1 VTVGMSIDIASIDMVSEVNMDYTLTMYFQQSWRDKRLAY-NGIPLNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNR 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  90 MLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHTT 169
Cdd:cd18999   80 MIRLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIESYGYTTDDIEFYWQGGDNAVTGVEKIELPQFSIVEYRLV 159

                        170       180
                 ....*....|....*....|....
gi 375493572 170 TKLAFYsSTGWYNRLYINFTLRRH 193
Cdd:cd18999  160 SREVVF-TTGSYPRLSLSFRLKRN 182

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 375493572  11 PVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSM-TFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNV 89
Cdd:cd18991    3 NVSVQIYINSIDSINEATMDYSVNIFLRQRWNDPRLNFTKLSNIDYlELDPKMIDKIWVPDLFFPNEKKANFHDVTVPNK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  90 MLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKgNDSLKTDERISLSQFLIQEFHTT 169
Cdd:cd18991   83 LLRIYPNGTVYYSMRLSLTLSCPMDLHKYPLDTQTCPIQIESFGYTTENLIFKWND-DKPVQLNDGLELPQFELKGVSTS 161

                        170       180
                 ....*....|....*....|...
gi 375493572 170 TKLAFYSSTGWYNRLYINFTLRR 192
Cdd:cd18991  162 DCTKTYTETGNFSCLEAKFHLQR 184

gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such as LCCH3 (ligand-gated chloride channel homolog 3); This family contains extracellular domain of beta-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster ligand-gated chloride channel homolog 3 (LCCH3) subunits. Drosophila melanogaster expresses three GABA-receptor subunit orthologs: (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila; LCCH3, ligand-gated chloride channel homolog 3), and may possibly form homo- and/or heteropentameric associations. LCCH3 has been shown to combine with subunit GRD to form cation-selective GABA-gated ion channels when coexpressed in Xenopus laevis oocytes. GABAARs are known to be the molecular targets of a class of insecticides. The resulting pentameric receptors in this family have been shown to be activated by insect GABA-receptor agonists muscimol and CACA, and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline. GABAARs are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  12 VGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTN-NLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNVM 90
Cdd:cd19006    4 VGMDLTIASFDSISEVNMDYTITMYLNQYWKDERLAFSIDNeSDVLTLSGDFAEKIWVPDTFFANDKNSFLHDVTERNKM 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  91 LRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKkgNDSLKTDERISLSQFLIQEFHTTT 170
Cdd:cd19006   84 VRLNGDGSITYGMRFTTTLACMMDLHYYPLDSQNCTVEIESYGYTVSDVVMYWK--NTPVRGVEDAELPQFTIIGYETND 161

                        170       180
                 ....*....|....*....|..
gi 375493572 171 KLAfYSSTGWYNRLYINFTLRR 192
Cdd:cd19006  162 RKE-KLATGSYQRLSLSFKLQR 182

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 375493572  10 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNnLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNV 89
Cdd:cd19003    2 VPVRISIYVSSIEQISEMNMDYTITMFFHQTWKDSRLAYYETT-LNLTLDYRMHEKLWVPDCYFLNSKDAFVHDVTVENR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  90 MLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHTT 169
Cdd:cd19003   81 VFQLHPDGTVRYGIRLTTTAACSLDLHKFPMDKQACKLEVESYGYTVEDIILFWEDNGNAIHMTEELHIPQFTFLGRTIT 160

                        170       180
                 ....*....|....*....|...
gi 375493572 170 TKLAFYsSTGWYNRLYINFTLRR 192
Cdd:cd19003  161 SKEVYF-YTGSYIRLILKFQVQR 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 375493572  10 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNnLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDNV 89
Cdd:cd19042    2 VCVGMNIDIASIDMVSEVNMDYTLTMYFQQYWRDKRLAYSGIP-LNLTLDNRVADQLWVPDTYFLNDKKSFVHGVTVKNR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  90 MLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEFHTT 169
Cdd:cd19042   81 MIRLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIESYGYTTDDIEFYWRGGDKAVTGVERIELPQFSIVEHRLV 160

                        170       180
                 ....*....|....*....|....
gi 375493572 170 TKLAFYsSTGWYNRLYINFTLRRH 193
Cdd:cd19042  161 SRNVVF-ATGAYPRLSLSFRLKRN 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 375493572  10 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNL-SMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTDN 88
Cdd:cd19008    1 VEVGVTMYVLSISSVSEVDMDFTLDFYFRQFWTDPRLAFKKSPGVeSLTVGSEFIKNIWVPDTFFPNEKQSYFHIATTSN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  89 VMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLKTDERISLSQFLIQEfHT 168
Cdd:cd19008   81 EFLRIHHSGSITRSIRLTITASCPMNLQYFPMDRQLCHIEIESFGYTMRDIRYKWNGGPNSVGISPEVELPQFKVLG-HR 159

                        170       180
                 ....*....|....*....|....
gi 375493572 169 TTKLAFYSSTGWYNRLYINFTLRR 192
Cdd:cd19008  160 QRAREISLTTGNYSRLACEIQFVR 183

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 375493572 196 FFLLQTYFPATLMVMLSWVSFWIDRRAVPARVPLGITTVLTMSTIITGVNASMPRVSYIKAVDIYLWVSFVFVFLSVLEY 275
Cdd:cd19049    1 YYLIQTYIPSILIVILSWVSFWIDPEAVPARVSLGITTVLTMTTQSSGVRSSLPKVSYVKAIDVWLGVCFVFVFAALLEY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572 276 AAVNYlttvqerkeqklreklpctsglppprtamldgnysdgevndldnympengekpdrmmvqltlasersspqrksqr 355
Cdd:cd19049   81 AVVNY--------------------------------------------------------------------------- 85

                        170       180       190
                 ....*....|....*....|....*....|...
gi 375493572 356 ssyvsmrIDTHAIDKYSRIIFPAAYILFNLIYW 388
Cdd:cd19049   86 -------LKASKIDRISRILFPLAFLIFNIIYW 111

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 375493572  12 VGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTNNLSMTFDGRLVKKIWVPDMFFVHSKRSFihDTTTDNVML 91
Cdd:cd03558    3 VTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFYNNKDAD--FVTTDNVLI 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  92 RVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGNDSLktDERISLSQFLIQEFHTTTK 171
Cdd:cd03558   81 RLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIELVWDSERPDQ--ADFLELPEWDIVEKRGRYC 158

                        170       180
                 ....*....|....*....|.
gi 375493572 172 LAFYsSTGWYNRLYINFTLRR 192
Cdd:cd03558  159 TVVY-NTGIYSDITYRFRLKR 178

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 375493572  10 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPST--NNLSMTFDGRLVKKIWVPDMFFVHSKRSFIHDTTTD 87
Cdd:cd19010    2 VDVVVNIFINSFGSIQETTMDYRVNIFLRQKWNDPRLKLPNDfrGSDALTVDPTMFKCLWKPDLFFANEKSANFHDVTQE 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375493572  88 NVMLRVQPDGKVLYSLRVTVTAMCNMDFSRFPLDTQTCSLEIESYAYTEDDLMLYWKKGnDSLKTdERISLSQFLIQ--- 164
Cdd:cd19010   82 NILLFIFRDGDVLVSMRLSITLSCPLDLTLFPMDTQRCKMQLESFGYTTDDLRFIWQSG-DPVQL-EKIALPQFDIKked 159

                        170       180       190
                 ....*....|....*....|....*....|
gi 375493572 165 -EFHTTTKlaFYSSTGWYNRLYINFTLRRH 193
Cdd:cd19010  160 iEYGNCTK--YYKGTGYYTCVEVIFTLRRQ 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.