The modulatory effects of the anxiolytic etifoxine on GABA(A)
receptors are mediated by the beta subunit

by
Hamon A, Morel A, Hue B, Verleye M, Gillardin JM.
Laboratoire de Neurophysiologie,
UPRES EA 2647 (RCIM),
Universite d'Angers, UFR Sciences,
2 Boulevard Lavoisier, F-49045 01,
Angers cedex, France
Neuropharmacology. 2003 Sep;45(3):293-303


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.
PTZ
GABA(A)
GABA(B)
GABA(C)
Buspirone
Alprazolam
Adinazolam
Barbiturates
Benzodiazepines
Future anxiolytics
Making animals cry
Anxiety and depression
Subthreshold syndromes
Better anti-anxiety drugs
Buspirone plus venlafaxine
Neuropepide Y and anxiety
Anxiolytics/antidepressants
Generalised Anxiety Disorder (GAD)
Neurobiology and genetics of anxiety
Anxioselective compounds and GABA(A)


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