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GABAA receptor; Benzodiazepine; Patch clamp; cDNA; Cell transfection
Abstract:
We compared the modulation of GABA (γ-aminobutyric acid)-activated currents by benzodiazepines in recombinant (GABAA receptors containing either one of two α subunits, α1 or α6. Lüddens et al. (Nature, 346 (1990) 648–651) have previously demonstrated that the α6 subunit is part of a cerebellar receptor subtype which selectively binds Ro15–4513, an antagonist of alcohol-induced motor ataxia. Here we report that the imidazobenzodiazepine Ro15–4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)benzodiazepine-3-carboxylate) reduced GABA-activated currents in recombinant α6β2γ2 and α1β2γ2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-β-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in α1β2γ2 receptors, but not in α6β2γ2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.
