Dual action of isoflurane on the gamma-aminobutyric acid (GABA)-mediated currents through recombinant alpha(1)beta(2)gamma(2L)-GABA(A)-receptor channels

Isoflurane (ISO) increased the agonist-induced chloride flux through the ga mma-aminobutyric acid A receptor (GABA(A)R). This may reflect an anesthetic -induced increase in the apparent agonist affinity. A dual effect of anesth etics was postulated for both the nicotinic acetylcholine receptor (nAChR) and the GABA(A)R. We tested the hypothesis that, in addition to a blocking effect, ISO increases gamma-aminobutyric acid (GABA)-gated currents through recombinant GABA(A)R channels. HEK293 cells were transfected with rat cDNA for alpha(1),beta(2),gamma(2L) subunits. Currents elicited by 1 mM or 0.01 mM GABA, respectively, alone, or with increasing concentrations of ISO, we re recorded by using standard patch clamp techniques. ISO reduced the peak current elicited by 1 mM GABA. Currents induced by 0.01 mM GABA were potent iated by small ISO (twofold at 0.5 mM ISO) and inhibited by larger concentr ations. Withdrawal of ISO and GABA induced rebound currents, suggesting an open-channel block by ISO. These currents increased with increasing concent rations of ISO. At large concentrations of ISO, the inhibitory effect predo minated and was caused by, at least partly, an open-channel block. At small concentrations of ISO, potentiation of the GABA-gated currents was more pr ominent. This dual action of ISO indicates different binding sites at the G ABA(A)R. The balance between potentiation and block depends on the concentr ations of both ISO and GABA.