Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in Xenopus oocytes:: Influence of α- and γ2-subunits

Propofol (2,6-diisopropylphenol) is an intravenous general anaesthetic which can directly activate and positively modulate the GABA(A) receptor. The effects of propofol on human recombinant GABA(A) receptors were studied in Xenopus oocytes expressing either alpha(1) beta(2), alpha(1) beta(2) gamma(2L), or alpha(2) beta(2) gamma(2L) receptor isoforms. In all receptor isoforms tested, propofol was able to potentiate the GABA-activated currents in a concentration-dependent manner. Although propofol potentiated both alpha(1) beta(2) and alpha(1) beta(2) gamma(2L) receptor isoforms with equal affinity, the efficacy of propofol potentiation was markedly greater in the alpha(1) beta(2) receptor isoform. In contrast, potentiation of the alpha(2) beta(2) gamma(2L) receptor isoform by propofol occurred with higher affinity and lower efficacy than in the alpha(1) beta(2) gamma(2L) receptor isoform. Propofol directly activated all three receptor isoforms in a concentration dependent manner. Addition of the gamma(2L) subunit subtype to the alpha(1) beta(2) receptor isoform decreased receptor sensitivity to direct activation by propofol. Replacement of the alpha(1)-subunit subtype with the alpha(2)-subunit subtype increased receptor sensitivity to propofol's direct effects. These results suggest that the alpha- and gamma(2L)-subunit subtypes each have the ability to influence both the direct and modulatory actions of propofol on GABA(A) receptor function. (C) 1998 Elsevier Science B.V.