Subunit-dependent block by isoflurane of wild-type and mutant α1S270H GABAA receptor currents in Xenopus oocytes

For all receptor combinations, at ≤0.6 mM isoflurane (≤2 minimum alveolar concentration (MAC)) current inhibitions were not pronounced (∼10%) with block reaching half-maximal levels at supraclinical concentrations (∼2 mM isoflurane, 6 MAC). Comparisons with other GABAA receptor blockers indicated that isoflurane blocks in a similar manner to picrotoxin, possibly via the pore of the receptor. The extent of isoflurane-induced inhibition was significantly attenuated by inclusion of the γ2s-subunit but was unaffected by introduction of the S270H mutation in the α1-subunit. In conclusion, isoflurane binds with low affinity and with subunit-specificity to an inhibitory site on the GABAA receptor that is distinct from the site that facilitates positive modulation at the extracellular end of the pore.