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

Abstract

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 α 1 β 2, α 1 β 2 γ 2L, or α 2 β 2 γ 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 α 1 β 2 and α 1 β 2 γ 2L receptor isoforms with equal affinity, the efficacy of propofol potentiation was markedly greater in the α 1 β 2 receptor isoform. In contrast, potentiation of the α 2 β 2 γ 2L receptor isoform by propofol occurred with higher affinity and lower efficacy than in the α 1 β 2 γ 2L receptor isoform. Propofol directly activated all three receptor isoforms in a concentration dependent manner. Addition of the γ 2L subunit subtype to the α 1 β 2 receptor isoform decreased receptor sensitivity to direct activation by propofol. Replacement of the α 1-subunit subtype with the α 2-subunit subtype increased receptor sensitivity to propofol's direct effects. These results suggest that the α-and γ 2L-subunit subtypes each have the ability to influence both the direct and modulatory actions of propofol on GABA A receptor function.