Electrophysiological actions of gamma-aminobutyric acid and clomethiazole on recombinant GABA(A) receptors

Clomethiazole is a gamma-aminobutyric acid (GABA)-mimetic agent with anticonvulsant, sedative and neuroprotective properties. The pharmacological actions of clomethiazole that underlie its functional profile have not been fully explored, but are known to result from an interaction with the GABA(A) receptor. Here, we present a quantitative electrophysiological study of clomethiazole action at human recombinant GABA(A) receptors. Whole-cell currents were recorded from murine L(tk-) cells stably transfected with either alpha1, beta1 and gamma 2 or alpha1, beta2 and gamma 2 GABA(A) receptor subunits. Clomethiazole directly activated GABA(A) currents in alpha1/beta1/gamma 2- and alpha1/beta2/gamma 2-containing cells, with EC(50) values of 0.3 and 1.5 mM, respectively. A low concentration of clomethiazole (30 micro M) also potentiated the action of GABA in both cell types, equivalent to a 3-fold increase in potency and up to 1.8-fold increase in maximal current. Both direct activation and gamma-aminobutyric acid potentiation are likely to contribute to the in vivo profile of clomethiazole.