Mutational analysis of molecular requirements for the actions of general anaesthetics at the γ-aminobutyric acidA receptor subtype, α1β2γ2

摘要

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.