The effects of a point mutation of the beta(2) subunit of GABA(A) receptoron direct and modulatory actions of general anesthetics

The gamma-aminobutyric acid type A receptor (GABA(A) receptor) sites involv ed 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) s ubunit (Tyr(157) --> Phe) affects the direct and modulatory actions of othe r general anesthetics such as propofol and etomidate. Using the two-electro de voltage clamp method, we recorded Cl- current in Xenopus oocytes express ing 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 pro pofol. However, the mutation had no effect on both the direct actions of pe ntobarbital and etomidate or on the modulatory actions of pentobarbital, pr opofol and etomidate. These results suggest that unique loci may exist for the direct action of propofol and that the GABA binding site map not mediat e the modulatory actions of general anesthetics at GABA(A) receptors. (C) 1 999 Elsevier Science B.V. All rights reserved.