The α5 GABAA receptor subunit confers resistance to isoflurane inhibition

The volatile anesthetic, isoflurane, potentiates and inhibits GABAA receptors (GABAARs)function at low and high concentrations, respectively. We examined whether the α subunit isoform influences isoflurane inhibition by studying currents generated by human recombinant α5/1β3γ2L GABAARs. The subunit isoforms selected for the study mediate a tonic (α5) and synaptic (α1) inhibitory conductance in hippocampal pyramidal neurons. The α5 subunit conferred partial resistance to isoflurane blockade compared with the α1 subunit. The steady-state current was preferentially reduced compared with the peak current suggesting that isoflurane inhibited GABAAR function by stabilizing an agonist-bound, closed conformational state or by a use-dependent steric blocking mechanism.