Abstract

Several previous studies implicated alpha 6 and gamma 2L subunits as potential determinants of gamma-aminobutyric acid A (GABAA) receptor channel sensitivity to alcohol modulation. The effects of ethanol and n-octanol were studied on GABA-induced currents in human embryonic kidney cells transfected to express one of three different GABAA receptor channel subunit combinations: alpha 1 beta 2 gamma 2S, alpha 6 beta 2 gamma 2S or alpha 6 beta 2 gamma 2L. No increase in the current amplitude of any subunit combination was observed after the coapplication of GABA and physiological concentrations (10-100 mM) of ethanol. By contrast, the coapplication of GABA and 100 microM octanol increased the current amplitude by 50% to 100% in all three subunit combinations. Octanol produced a shift of the current dose-response curve toward lower concentrations of GABA. Ethanol was effective in increasing the rate of desensitization produced by higher concentrations of GABA in the alpha 6 beta 2 gamma 2S cells but not the alpha 1 beta 2 gamma 2S combination. This ethanol-induced modification of desensitization was not altered by the presence of the protein kinase inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). These experiments indicate that the presence of alpha 6 or gamma 2L subunits, in itself, does not result in the potentiation of GABA-induced currents by ethanol, as described in some reports. However, the presence of either the alpha 6 or alpha 1 subunit may determine whether the desensitization rate of the GABAA current is affected by the alcohol.