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Understanding subtype-selective allosteric modulation of GABAA receptors

BMC Pharmacology and Toxicology
Springer (Biomed Central Ltd.)
Publication Date
DOI: 10.1186/2050-6511-13-s1-a26
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  • Biology


Understanding subtype-selective allosteric modulation of GABAA receptors MEETING ABSTRACT Open Access Understanding subtype-selective allosteric modulation of GABAA receptors Roshan Puthenkalam, Zdravko Varagić, Pantea Mirheydari, Werner Sieghart, Margot Ernst* From 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint meeting with the Croatian, Serbian and Slovenian Pharmacological Societies. Graz, Austria. 20-21 September 2012 Background The g-aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors of the central nervous system. Benzodiazepine (Bz)-site ligands bind at the a/g interface and can enhance GABA-induced Cl− cur- rents. The efficacy of certain benzodiazepines strongly depends on the type of a(1,2,3,5) subunits in the receptors. Functionally selective compounds for a2/3 can be anxioly- tic without having the side effect of sedation. The molecular basis for functional selectivity is investigated in this work. Methods Two-electrode voltage-clamp electrophysiology recordings were performed in wild-type and mutated receptors expressed in Xenopus laevis oocytes. Modelling, docking and molecular dynamics simulation studies of a1g2 and a3g2-containing receptors were performed to understand Bz-ligand interaction with the different a subunits. Results Electrophysiology recordings identified flumazenil as a null modulator in a1 and a weak plus modulator in a3- containing receptors. A sequence comparison between the a1 and a3 subunit revealed the residue R228 as unique for the a3 subunit among all a subunits. a3R228A- mutated receptors completely lost their ability to respond to flumazenil. This amino acid is part of the so-called loop C, a several-residues-spanning segment that forms part of the ligand-binding site with a highly variable sequence. The functionally a3-selective ligand flumazenil was docked into the a/g interface. The flumazenil-bound state in the a1 subtype has already been studied previously

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