Isoflurane slows inactivation kinetics of rat recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors: enhancement of GABAergic transmission despite an open-channel block

Recombinant alpha (1)beta (2)gamma (2L) gamma -aminobutyric acid (A) recept or (GABA(A)R) channels expressed in human embryonic kidney (HEK293) cells w ere used for patch-clamp experiments. The currents activated by brief pulse s of GABA (10(-4) M) applied with a device for fast solution exchange to ce lls clamped in the whole-cell configuration mimicked GABA(A)R-mediated inhi bitory postsynaptic currents. Isoflurane (ISO) at clinically relevant conce ntrations (0.6 mM) decreased the amplitude and prolonged the decay of the G ABA-evoked response. To further detail the mechanism underlying the prolong ed decay time, we made simulations based on these measurements. These simul ations suggest that ISO slows the rate of GABA unbinding from the receptor. Under these conditions, ISO increases the GABA-induced charge transfer and , thus, could enhance GABAergic inhibition despite the concomitant open-cha nnel block causing the decrease in the current amplitude. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.