Abstract

The effects of subunit composition of the γ-aminobutyric acid (GABA) type A receptor on the multiple actions of the general anesthetics alphaxalone and etomidate were investigated. The abilities of the two drugs to activate directly Cl⁻ currents and to modulate GABA-evoked Cl⁻ currents mediated by human recombinant GABA_A receptors composed of α1, γ2S, and either β1, β2, or β3 subunit expressed in Xenopus laevisoocytes were compared. Both alphaxalone and etomidate evoked Cl⁻ currents in α1β1γ2S, α1β2γ2S, and α1β3γ2S receptors, an action that was blocked by both SR 95531 and picrotoxin. However, although maximal current activation by alphaxalone varied only slightly with the specific β subunit isoform present, the efficacy of etomidate showed a rank order of β3 > β2 ≫> β1. In addition, β1 homomeric receptors were markedly activated by etomidate but not by alphaxalone. Conversely, receptors consisting of α1 and γ2S subunits were markedly activated by alphaxalone but not by etomidate. The modulatory effect of alphaxalone was also not markedly influenced by the β-specific subunit isoform, whereas the modulatory efficacy of etomidate showed a rank order of β3 > β2 ≫ β1. These results further demonstrate that the actions of general anesthetics at GABA_A receptors are influenced by receptor subunit composition, and they suggest that the effects of alphaxalone and etomidate are mediated by different binding sites on the receptor complex.