title: Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5.
abstract: GABA is the main inhibitory neurotransmitter in the mammalian central nervous system. When GABA binds to the ubiquitous GABA-A receptors on neurons, chloride channels are activated leading to a rapid increase in chloride conductance that depresses excitatory depolarization. The GABA-A receptors are targets for many clinically important drugs, such as the benzodiazepines, general anaesthetics, and barbiturates. All of these drugs enhance the chloride current activated by GABA. Of the GABA-A receptor family, the subtype 2 is critical for the treatment of anxiety spectrum disorders. To avoid unwanted side effects, it is necessary to find highly selective drugs that interact only with subtype 2 but not with the related receptors such as subtypes 1, 3, and 5. To realize such a goal, it is important to have not only the 3D (dimensional) structure of subtype 2 but also the 3D structures of subtypes 1, 3, and 5. In this study, the 3D structures of all the four subtypes of GABA-A receptors have been derived. The computer-modeled heteropentameric structures bear the following features: (1) each of the five subunits in the pentamer has an intrachain disulfide bond, a hallmark of ligand-gated pentameric channels; (2) those residues which are sensitive to the binding of the benzodiazepine site ligands are grouped around the alpha1,2,3,5/gamma2 interfaces; and (3) those residues which are sensitive to the binding of GABA molecules are grouped around the alpha1,2,3,5/beta2 interfaces. All these findings are fully consistent with experimental observations. Meanwhile, for those sensitive or key residues, a close look at their subtle difference among the four subtypes has been provided through a highlighted superposition picture. In addition to providing the atomic coordinates, the predicted structures have further clarified some ambiguities that could not been uniquely determined by the existing experimental data, such as the directionality of the subunit arrangement in the heteropentamers. The 3D models may provide a reasonable structural frame or footing for designing highly selective drugs. The present models might be also useful in understanding the basic mechanism of operation of the GABA-A receptors, stimulating novel strategies for developing more specific drugs and better treatments.
authors.affiliation: Tianjin Institute of Bioinformatics and Drug Discovery, Tianjin 300074, China. kchou@san.rr.com
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004594:Electrophysiology; D006801:Humans; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry; D008954:Models, Biological; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D008974:Mollusca; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011963:Receptors, GABA-A / Q000737:chemistry*
chemical_list: D002712:Chlorides; D004220:Disulfides; D008024:Ligands; D008051:Lipid Bilayers; D011963:Receptors, GABA-A; D001569:Benzodiazepines