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

Abstract

Background and objective The γ1-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 α1β1γ1 GABA_AR channels was studied (patch clamp; HEK293 cells). GABA 0.01mM or 1mM was applied alone or together with sevoflurane (0.05mM to 5mM).

Results Currents elicited by GABA 0.01mM were increased by low sevoflurane concentrations to 183% and decreased by high sevoflurane concentrations (> 1mM) to 34% (P < 0.05). Ten- to 90%-rise times of the currents were reduced by sevoflurane concentration dependently. At GABA (1mM), 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 openchannel 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 (0.01mM). 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.