extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. 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 this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHH-DSIWTPDTYFIMHGDFKD-PIIPMH 464
Cdd:cd18987    1 TNVKVSIYIESISSIDEQTMDFTVDMYLRQRWTDPRLAYPDRNGTDPILLPSDKfDKIWLPDLYFRNEKSSSFhDVTTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 465 FALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSLTTLNAYLIKNQT 544
Cdd:cd18987   81 VLVRIFPNGTVLYSQRLTLTLSCPMNLQKFPFDTQVCTLRLESYGYTTDQVVLHWDDDPPIVVNESSLLLPEFSLVKITT 160

                        170       180
                 ....*....|....*....|....*
gi 386771194 545 TACDQN-SWRGNYSCLQVELTFTRD 568
Cdd:cd18987  161 SDCTGNySTTGNYSCLEATFKLKRE 185

extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. 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 this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHH-DSIWTPDTYFIMHGDFKD-PIIPMH 464
Cdd:cd18987    1 TNVKVSIYIESISSIDEQTMDFTVDMYLRQRWTDPRLAYPDRNGTDPILLPSDKfDKIWLPDLYFRNEKSSSFhDVTTPN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 465 FALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSLTTLNAYLIKNQT 544
Cdd:cd18987   81 VLVRIFPNGTVLYSQRLTLTLSCPMNLQKFPFDTQVCTLRLESYGYTTDQVVLHWDDDPPIVVNESSLLLPEFSLVKITT 160

                        170       180
                 ....*....|....*....|....*
gi 386771194 545 TACDQN-SWRGNYSCLQVELTFTRD 568
Cdd:cd18987  161 SDCTGNySTTGNYSCLEATFKLKRE 185

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 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNaLHHH--DSIWTPDTYFIMH--GDFKDPIIP 462
Cdd:cd18991    2 TNVSVQIYINSIDSINEATMDYSVNIFLRQRWNDPRLNFTKLSNIDYLE-LDPKmiDKIWVPDLFFPNEkkANFHDVTVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 463 --MhfaLRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWkNDEDTLRKSPSLTTLNAYLI 540
Cdd:cd18991   81 nkL---LRIYPNGTVYYSMRLSLTLSCPMDLHKYPLDTQTCPIQIESFGYTTENLIFKW-NDDKPVQLNDGLELPQFELK 156

                        170       180
                 ....*....|....*....|....*....
gi 386771194 541 KNQTTACDQN-SWRGNYSCLQVELTFTRD 568
Cdd:cd18991  157 GVSTSDCTKTyTETGNFSCLEAKFHLQRN 185

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 386771194  338 KEILDLLLEkkRYDKRLLPPVNDEDfccglqspdmatnqnarrphnrgTLTVNVNVLLLSLASPDESSLKYEVEFLLNQQ 417
Cdd:pfam02931   2 ERLLDDLLS--GYDKLVRPVANGSD-----------------------PVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQT 56

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194  418 WNDPRLQYgNKSHYDFLNALHH-HDSIWTPDTYFIMHGDFKDPI-IPMHFaLRIFRNGTITYAMRRHLILSCQGSLHIFP 495
Cdd:pfam02931  57 WTDPRLAW-NPEDYGGITSLRLpSDKIWKPDIVLYNKADGIHEVtTPNTN-VRVYYDGTVLWSPPAIYKSSCSIDVTYFP 134

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 386771194  496 FDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSltTLNAYLIKNQTTACDQNSWR-----GNYSCLQVELTFT 566
Cdd:pfam02931 135 FDEQNCSLKFGSWTYNGEEVDLRWDDDPPVVELEEI--DLSDFWLNGEWDIVDVPAKRreypyGCYSELTGDVTFY 208

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 386771194 571 YYFTTVFIPGIILVTSSFITFWLEWNAVPARVMIGVTTMLNFFTTSNGFRSTLPVVSNLTAMNVWDGVCMCFIYASLLEF 650
Cdd:cd19062    1 FYLLQLYIPSCMLVIVSWVSFWIDWTAVPGRVTLGVTTLLTMTTQSAGINAKLPPVSYIKAIDVWIGACVTFVFGALLEF 80

                         90
                 ....*....|....*...
gi 386771194 651 VCVNYVGRKRPLHNVVYR 668
Cdd:cd19062   81 AFVNYAGNRAKRIDLISR 98

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 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHHDSIWTPDTYFI--MHGDFKDPIIPMh 464
Cdd:cd03558    1 VTVTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFYnnKDADFVTTDNVL- 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 465 faLRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDedtlrkSPSL---TTLNAYLIK 541
Cdd:cd03558   80 --IRLSPDGTVLYSPRAILKSACPMDLKRFPFDQQNCTMKLESWTYDTTDIELVWDSE------RPDQadfLELPEWDIV 151

                        170       180
                 ....*....|....*....|....*..
gi 386771194 542 NQT-TACDQNSWRGNYSCLQVELTFTR 567
Cdd:cd03558  152 EKRgRYCTVVYNTGIYSDITYRFRLKR 178

extracellular domain of histimine-gated chloride channel (HisCl or HGCC); This family contains extracellular domain (ECD) of histamine-gated chloride channel (HisCl), a member of the Cys-loop receptor superfamily of ligand-gated ion channels and is closely related to the mammalian GABAA receptor and glycine receptor (GlyR). Histamine (HA) is a neurotransmitter that activates GPCRs in vertebrates, but in arthropods, it is a photoreceptor neurotransmitter, directly gating chloride channels on large monopolar cells (LMCs), postsynaptic to photoreceptors in the lamina. It has also been reported to play important roles in mechanosensory reception, temperature preference, and sleep in insects. HA activates its receptor channels to cause an inward chloride flux in the insect nervous system. In Drosophila, HA acts on two histamine-gated chloride channel (HGCC) subunits called HisCl1 (HisClalpha2, HCLB) and HisCl2 (HisClalpha1, Ort, HCLA). HisCl1 (HCLB) and HisCl2 (HCLA) are expressed predominantly in the insect eye, sharing 60% sequence identity, and forming homomeric and heteromeric HGCCs. HCLA homomers are involved in synaptic transmission in the lamina, while HCLB homomers, localized in the glia cells, have a role in shaping the transmission. HCLB channels, but not HCLA channels, are also responsible for the activation and maintenance of wake state in D. melanogaster. In Manduca sexta, HCLB channels in the flight sensory-motor have been shown to be involved in olfactory processing circuit. Studies show that HCLB channels are more sensitive to agonists when compared with HCLA channels, but insensitive to known LGCC insecticides.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 389 VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNK--SHYDFLNA--LHhhdSIWTPDTYF--IMHGDFKDPIIP 462
Cdd:cd18992    5 VYFHVTVMGLDSIDEESMTYVADIFFAQSWRDHRLRLPENmtSEYRLLDVdwLK---NIWRPDSFFknAKSVTFHTMTIP 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 463 MHFaLRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWkNDEDTLRKSPSLTTLNAYLIKN 542
Cdd:cd18992   82 NHY-LWLYKDKTILYMVKLTLVLSCAMNFEIYPHDTQECKLQIESLSHTTDDLVFQW-DPDVPLVVDENIELPQLQLSNN 159

                        170       180
                 ....*....|....*....|....*
gi 386771194 543 QTTACDQNSWRGNYSCLQVELTFTR 567
Cdd:cd18992  160 YTADCTQVYSTGNFTCLEVVFVLKR 184

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 386771194 572 YFT-TVFIPGIILVTSSFITFWLEWNAVPARVMIGVTTMLNFFTTSNGFRSTLPVVSNLTAMNVWDGVCMCFIYASLLEF 650
Cdd:cd19054    1 YFTiQTYIPCILTVVLSWVSFWINKDAVPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFAALMEY 80

                 ....*
gi 386771194 651 VCVNY 655
Cdd:cd19054   81 GTLHY 85

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 386771194 389 VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNkshyDFLNA------LHHHDSIWTPDTYFI--MHGDFKDpI 460
Cdd:cd19010    4 VVVNIFINSFGSIQETTMDYRVNIFLRQKWNDPRLKLPN----DFRGSdaltvdPTMFKCLWKPDLFFAneKSANFHD-V 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 461 IPMHFALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSLTTLNAYLI 540
Cdd:cd19010   79 TQENILLFIFRDGDVLVSMRLSITLSCPLDLTLFPMDTQRCKMQLESFGYTTDDLRFIWQSGDPVQLEKIALPQFDIKKE 158

                        170       180
                 ....*....|....*....|....*...
gi 386771194 541 KNQTTACDQ-NSWRGNYSCLQVELTFTR 567
Cdd:cd19010  159 DIEYGNCTKyYKGTGYYTCVEVIFTLRR 186

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 386771194 377 NARRPHNRGTLT-VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHhDSIWTPDTYFimHGD 455
Cdd:cd19035    9 NRLRPGLGDSITeVFTNIYVTSFGPVSDTDMEYTIDVFFRQRWKDERLKFKGPMNILRLNNLMA-SKIWTPDTFF--HNG 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 456 FKDPIIPMHFA---LRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVW-KNDEDTLRKSPS 531
Cdd:cd19035   86 KKSVAHNMTMPnklLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSCPLKFGSYAYTTSEVTYIWtYNASDSVQVAPD 165

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 386771194 532 LTTLNAYLIKNQTTACDQ-NSWRGNYSCLQVELTFTR 567
Cdd:cd19035  166 GSRLNQYDLLGQTIGKETiKSSTGEYTVMTAHFHLKR 202

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 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQY-GNKSHYdfLNAlHHHDSIWTPDTYFI-MHGDFKDPIIPMH 464
Cdd:cd19004    2 VTVGMSLDIASIDTISEINMDYTATIFLRQRWTDERLCFeGNKSLS--LDG-RLVELLWVPDTFIVdSKKSFLHDITVEN 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 465 FALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSLtTLNAYLIKNQT 544
Cdd:cd19004   79 RLIRIFPNGTVLYALRITTTVACSMDLTKYPMDKQTCTLQLESWGYNINDVMFYWTRGNDSVRGLDHL-RLAQYTVEDYF 157

                        170       180
                 ....*....|....*....|....*
gi 386771194 545 TACDQNSWR-GNYSCLQVELTFTRD 568
Cdd:cd19004  158 TSVSEAVYEtGNYPKLVFHFELKRN 182

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 386771194 572 YFTTVFIPGIILVTSSFITFWLEWNAVPARVMIGVTTMLNFFTTSNGFRSTLPVVSNLTAMNVWDGVCMCFIYASLLEFV 651
Cdd:cd19055    2 YIIQSYMPSILLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSSLPRASAIKALDVYFWICYVFVFAALVEYA 81

                         90
                 ....*....|..
gi 386771194 652 CVNY-VGRKRPL 662
Cdd:cd19055   82 FAHYnADYRRPI 93

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 386771194 387 LTVNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHHDSIWTPDTYFIMHG-DFKDPIIPMHF 465
Cdd:cd19047    2 IPVGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTTNKSMTFDGRLVKKIWVPDVFFVHSKrSFIHDTTTDNI 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 466 ALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLRKSPSLtTLNAYLIK--NQ 543
Cdd:cd19047   82 MLRVFPDGHVLYSMRITVTAMCNMDFSRFPLDSQTCSLELESYAYTDEDLMLYWKNGNESLKTDEKI-SLSQFLIQkfHT 160

                        170       180
                 ....*....|....*....|....
gi 386771194 544 TTACDQNSWRGNYSCLQVELTFTR 567
Cdd:cd19047  161 TSRLAFYSSTGWYNRLYINFTLRR 184

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 386771194 571 YYFTTVFIPGIILVTSSFITFWLEWNAVPARVMIGVTTMLNFFTTSNGFRSTLPVVSNLTAMNVWDGVCMCFIYASLLEF 650
Cdd:cd19053    1 YFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIPYVKAIDMYLMGCFVFVFLALLEY 80

                 ....*.
gi 386771194 651 VCVNYV 656
Cdd:cd19053   81 AFVNYI 86

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 386771194 389 VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHHDSIWTPDTYFI------MHGDFKDPIIp 462
Cdd:cd19005    4 VGVDVQVESLDSISEVDMDFTMTLYLRHYWKDERLSFPSTANKSMTFDGRLVKKIWVPDVFFVhskrsfIHDTTTDNIM- 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 463 mhfaLRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDEDTLrKSPSLTTLNAYLIK- 541
Cdd:cd19005   83 ----LRVFPDGHVLYSLRITVTAMCNMDFSRFPLDTQTCSLELESYAYTEDDLMLYWKNGNESL-KTDEKISLSQFLIQk 157

                        170       180
                 ....*....|....*....|....*..
gi 386771194 542 -NQTTACDQNSWRGNYSCLQVELTFTR 567
Cdd:cd19005  158 fHTTSRLAFYSSTGWYNRLYINFTLRR 184

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3 or GABRA3); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3), a protein that is encoded by the GABRA3 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-3 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha3betagamma2, typically found post-synaptically. Rare loss-of-function variants in GABRA3 have been shown to increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay, and dysmorphic features. GABRA3, normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression being inversely correlated with breast cancer survival. It activates the AKT pathway to promote breast cancer cell migration, invasion, and metastasis. GABRA3 promotes lymphatic metastasis in lung adenocarcinoma by mediating upregulation of matrix metalloproteinases, MMP-2 and MMP-9, through activation of the JNK/AP-1 signaling pathway. GABRA3 is overexpressed in human hepatocellular carcinoma growth and, with GABA, promotes the proliferation of cancer cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 377 NARRPHNRGTLT-VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHhDSIWTPDTYFimHGD 455
Cdd:cd19036    6 NRLRPGLGDSVTeVKTDIYVTSFGPVSDTDMEYTIDVFFRQSWRDERLKFDGPMKILPLNNLLA-SKIWTPDTFF--HNG 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 456 FKDPIIPM---HFALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKN-DEDTLRKSPS 531
Cdd:cd19036   83 KKSVAHNMttpNKLLRLVDNGTLLYTMRLTIHAECPMHLEDFPMDVHACPLKFGSYAYTKTEVVYSWTLgKNKSVEVAPD 162

                 ....*..
gi 386771194 532 LTTLNAY 538
Cdd:cd19036  163 GSRLNQY 169

extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5 or GABRA5); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5), a protein that is encoded by the GABRA5 gene in humans, with biased expression in the brain and heart. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-5 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha5-beta-gamma2, and probably alpha5-beta3-gamma2, predominantly expressed in the hippocampus and localized extrasynaptically. These receptors have been demonstrated to play an important modulatory role in learning and memory processes, thus making them suitable targets for pharmacological intervention. Studies show that alpha5-containing GABAARs play an important part in tonic inhibition in hippocampal pyramidal neurons, and that these can also contribute to synaptic inhibition. Studies strongly suggest that amnesia is primarily mediated by alpha5-beta-gamma2. Polymorphisms in GABRA5 (and GABRA3) are linked to the susceptibility to panic disorder. A genetic association also exists between GABRA5 and bipolar affective disorder.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 389 VNVNVLLLSLASPDESSLKYEVEFLLNQQWNDPRLQYGNKSHYDFLNALHHhDSIWTPDTYF------IMHGdfkdpIIP 462
Cdd:cd19038   18 VRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRFKGPMQRLPLNNLLA-SKIWTPDTFFhngkksIAHN-----MTT 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386771194 463 MHFALRIFRNGTITYAMRRHLILSCQGSLHIFPFDDPKCSFSMESISYEEAQIKYVWKNDED-TLRKSPSLTTLNAYLIK 541
Cdd:cd19038   92 PNKLLRLEDDGTLLYTMRLTISAECPMQLEDFPMDAHACPLKFGSYAYPNSEVVYVWTNGTTkSVVVAEDGSRLNQYHLM 171