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 (GAB A) 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 alpha 1, gamma 2S, and either beta 1, beta 2, or beta 3 subunit expre ssed in Xenopus laevis oocytes were compared. Both alphaxalone and eto midate evoked Cl- currents in alpha 1 beta 1 gamma 2S, alpha 1 beta 2 gamma 2S, and alpha 1 beta 3 gamma 2S receptors, an action that was bl ocked by both SR 95531 and picrotoxin. However, although maximal curre nt activation by alphaxalone varied only slightly with the specific be ta subunit isoform present, the efficacy of etomidate showed a rank or der of beta 3 > beta 2 >>> beta 1. In addition, beta 1 homomeric recep tors were markedly activated by etomidate but not by alphaxalone. Conv ersely, receptors consisting of alpha 1 and gamma 2S subunits were mar kedly activated by alphaxalone but not by etomidate. The modulatory ef fect of alphaxalone was also not markedly influenced by the beta-speci fic subunit isoform, whereas the modulatory efficacy of etomidate show ed a rank order of beta 3 > beta 2 much greater than beta 1. These res ults further demonstrate that the actions of general anesthetics at GA BA(A) receptors are influenced by receptor subunit composition, and th ey suggest that the effects of alphaxalone and etomidate are mediated by different binding sites on the receptor complex.