Mutational analysis of molecular requirements for the actions of general anaesthetics at the γ-aminobutyric acid(A )receptor subtype, α1β2γ2

BACKGROUND: Amino acids in the β subunit contribute to the action of general anaesthetics on GABA(A )receptors. We have now characterized the phenotypic effect of two β subunit mutations in the most abundant GABA(A )receptor subtype, α1β2γ2. RESULTS: The β2(N265M) mutation in M2 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, while the direct actions of propofol, etomidate and alphaxalone were impaired. The β2(M286W) mutation in M3 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, whereas the direct action of propofol and etomidate, but not of alphaxalone, was impaired. CONCLUSIONS: We found that the actions of general anaesthetics at α1β2(N265M)γ2 and α1β2(M286W)γ2 GABA(A )receptors are similar to those previously observed at α2β3(N265M)γ2 and α2β3(M286W)γ2 GABA(A )recpetors, respectively, with the notable exceptions that the direct action of propofol was decreased in α1β2(M286W)γ2 receptors but indistinguishable form wild type in α2β3(M286W)γ2 receptors and that the direct action of alphaxalone was decreased in α1β2(N265M)γ2 but not α2β3(N265M)γ2 receptors and indistinguishable form wild type in α1β2(M286W)γ2 receptors but increased in α2β3(M286W)γ2 receptors. Thus, selected phenotypic consequences of these two mutations are GABA(A )receptor subtype-specific.