title: Inverse but not full benzodiazepine agonists modulate recombinant alpha 6 beta 2 gamma 2 GABAA receptors in transfected human embryonic kidney cells.
abstract: We compared the modulation of GABA (gamma-aminobutyric acid)-activated currents by benzodiazepines in recombinant GABAA receptors containing either one of two alpha subunits, alpha 1 or alpha 6. Lüddens et al. (Nature, 346 (1990) 648-651) have previously demonstrated that the alpha 6 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 alpha 6 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in alpha 1 beta 2 gamma 2 receptors, but not in alpha 6 beta 2 gamma 2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.
authors.affiliation: Department of Neurobiology, University of Heidelberg, F.R.G.
authors.forename: C
authors.initials: C
authors.lastname: Kleingoor
authors.forename: M
authors.initials: M
authors.lastname: Ewert
authors.forename: G
authors.initials: G
authors.lastname: von Blankenfeld
authors.forename: P H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: H
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001386:Azides; D002243:Carbolines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C042957:Ro 15-4513