Differential subunit dependence of the actions of the general anesthetics alphaxalone and etomidate at gamma-aminobutyric acid type A receptors expressed in Xenopus laevis oocytes.

The effects of subunit composition of the gamma-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 alpha1, gamma2S, and either beta1, beta2, or beta3 subunit expressed in Xenopus laevis oocytes were compared. Both alphaxalone and etomidate evoked Cl currents in alpha1 beta1 gamma2S, alpha1 beta2 gamma2S, and alpha1 beta3 gamma2S 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 beta subunit isoform present, the efficacy of etomidate showed a rank order of beta3 > beta2 >>> beta1. In addition, beta1 homomeric receptors were markedly activated by etomidate but not by alphaxalone. Conversely, receptors consisting of alpha1 and gamma2S subunits were markedly activated by alphaxalone but not by etomidate. The modulatory effect of alphaxalone was also not markedly influenced by the beta-specific subunit isoform, whereas the modulatory efficacy of etomidate showed a rank order of beta3 > beta2 >> beta1. 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.