Sevoflurane potentiates and blocks GABA-induced currents through recombinant α₁β₂γ₂ GABA_A receptors: Implications for an enhanced GABAergic transmission

Background and objective: The γ-aminobutyric acid_A receptor (GABA_AR) is a target for anaesthetic agents. We investigated the interactions of sevoflurane with a recombinant GABA_AR. Emphasis was on the mechanism of block, as relevant open-channel block by a volatile anaesthetic would possibly explain prolonged GABAergic postsynaptic currents. Methods: The effect of sevoflurane on GABA-induced currents through recombinant α₁β₂γ₂ GABA_AR channels was studied (patch clamp; HEK293 cells). GABA 0.01 mM or 1 mM was applied alone or together with sevoflurane (0.05 mM to 5 mM). Results: Currents elicited by GABA 0.01 mM were increased by low sevoflurane concentrations to 183% and decreased by high sevoflurane concentrations (> 1 mM) to 34% (P < 0.05). Ten- to 90%-rise times of the currents were reduced by sevoflurane concentration dependently. At GABA (1 mM), peak currents and 10-90%-rise times decreased with increasing sevoflurane concentrations. A transient current increase was induced by discontinuation of GABA and sevoflurane. Such rebound currents indicate a reversal of an open-channel block by sevoflurane. Conclusions: Sevoflurane (a) increases the apparent affinity of GABA to the GABA_AR, as suggested by the decreased current rise times. This explains the enhancement of the currents induced by low GABA concentrations (0.01 mM). Additionally, sevoflurane (b) induces a picrotoxin-like open-channel block at the GABA_AR. The reversal of the open-channel block elicits a delayed GABA response. These findings indicate at least two different sites of action of sevoflurane at this receptor that are both important for an enhanced GABAergic synaptic transmission.