title: The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit.
abstract: The anxiolytic compound etifoxine (2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride) potentiates GABA(A) receptor function in cultured neurons (Neuropharmacology 39 (2000) 1523). However, the molecular mechanisms underlying these effects are not known. In this study, we have determined the influence of GABA(A) receptor subunit composition on the effects of etifoxine, using recombinant murine GABA(A) receptors expressed in Xenopus oocytes. Basal chloride currents mediated by homomeric beta receptors were reduced by micromolar concentrations of etifoxine, showing that beta subunits possess a binding site for this modulator. In oocytes expressing alpha(1)beta(x) GABA(A) receptors (x=1, 2 or 3), etifoxine evoked a chloride current in the absence of GABA and enhanced GABA (EC10)-activated currents, in a dose-dependent manner. Potentiating effects were also observed with alpha(2)beta(x), beta(x)gamma(2s) or alpha(1)beta(x)gamma(2s) combinations. The extent of potentiation was clearly beta-subunit-dependent, being more pronounced at receptors containing a beta(2) or a beta(3) subunit than at receptors incorporating a beta(1) subunit. The mutation of Asn 289 in the channel domain of beta(2) to a serine (the homologous residue in beta(1)) did not significantly depress the effects of etifoxine at alpha(1)beta(2) receptors. This specific pattern of inhibition/potentiation was compared with that of other known modulators of GABA(A) receptor function like benzodiazepines, neurosteroids, barbiturates or loreclezole.
authors.affiliation: Laboratoire de Neurophysiologie, UPRES EA 2647 (RCIM), Université d'Angers, UFR Sciences, 2 Boulevard Lavoisier, F-49045 01, Angers cedex, France. alain.hamon@univ-angers.fr
authors.forename: Alain
authors.initials: A
authors.lastname: Hamon
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.forename: Bernard
authors.initials: B
authors.lastname: Hue
authors.forename: Marc
authors.initials: M
authors.lastname: Verleye
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Gillardin
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D010078:Oxazines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C002125:etifoxine