The effects of a point mutation of the β2 subunit of GABAA receptor on direct and modulatory actions of general anesthetics

The gamma-aminobutyric acid type A receptor (GABA(A) receptor) sites involved in the direct and modulatory actions of general anesthetics remain to be elucidated. The mutation of tyrosine at position 157 in the beta(2) GABA(A) receptor subunit was reported to reduce sensitivity to activation by GABA, but not pentobarbital. We examined whether this mutation of the beta(2) subunit (Tyr(157) --> Phe) affects the direct and modulatory actions of other general anesthetics such as propofol and etomidate. Using the two-electrode voltage clamp method, we recorded Cl- current in Xenopus oocytes expressing alpha(1)beta(2)gamma(2s) and alpha(1)-mutated beta(2)gamma(2s) subunits. The mutation of the beta(2) subunit reduced the apparent affinity for propofol. However, the mutation had no effect on both the direct actions of pentobarbital and etomidate or on the modulatory actions of pentobarbital, propofol and etomidate. These results suggest that unique loci may exist for the direct action of propofol and that the GABA binding site map not mediate the modulatory actions of general anesthetics at GABA(A) receptors. (C) 1999 Elsevier Science B.V. All rights reserved.