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

BACKGROUND Amino acids in the beta subunit contribute to the action of general anaesthetics on GABA(A) receptors. We have now characterized the phenotypic effect of two beta subunit mutations in the most abundant GABA(A) receptor subtype, alpha1beta2gamma2. RESULTS The beta2(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 beta2(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 alpha1beta2(N265M)gamma2 and alpha1beta2(M286W)gamma2 GABA(A) receptors are similar to those previously observed at alpha2beta3(N265M)gamma2 and alpha2beta3(M286W)gamma2 GABA(A) recpetors, respectively, with the notable exceptions that the direct action of propofol was decreased in alpha1beta2(M286W)gamma2 receptors but indistinguishable form wild type in alpha2beta3(M286W)gamma2 receptors and that the direct action of alphaxalone was decreased in alpha1beta2(N265M)gamma2 but not alpha2beta3(N265M)gamma2 receptors and indistinguishable form wild type in alpha1beta2(M286W)gamma2 receptors but increased in alpha2beta3(M286W)gamma2 receptors. Thus, selected phenotypic consequences of these two mutations are GABA(A) receptor subtype-specific.