Abstract

GABA_A receptors are predominantly composed of αβγ and αβδ isoforms in the brain. It has been proposed that αβγ receptors mediate phasic inhibition, whereas αβδ receptors mediate tonic inhibition. Propofol (2,6-di-isopropylphenol), a widely used anesthetic drug, exerts its effect primarily by modulating GABA_A receptors; however, the effects of propofol on the kinetic properties of αβγ and αβδ receptors are uncertain. We transfected human embryonic kidney (HEK293T) cells with cDNAs encoding rat α1, α6, β3, γ2L, or δ subunits and performed whole-cell patch-clamp recordings to explore this issue. Propofol (3 μM) increased GABA concentration-response curve maximal currents similarly for both α1β3γ2L and α6β3γ2L receptors, but propofol increased those for α1β3δ and α6β3δ receptors differently, the increase being greater for α1β3δ than for α6β3δ receptors. Propofol (10 μM) produced similar alterations in α1β3γ2L and α6β3γ2L receptor currents when using a preapplication protocol; peak currents were not altered, desensitization was reduced, and deactivation was prolonged. Propofol enhanced peak currents for both α1β3δ and α6β3δ receptors, but the enhancement was greater for α1β3δ receptors. Desensitization of these two isoforms was not modified by propofol. Propofol did not alter the deactivation rate of α1β3δ receptor currents but did slow deactivation of α6β3δ receptor currents. The findings that propofol reduced desensitization and prolonged deactivation of γ2L subunit-containing receptors and enhanced peak currents or prolonged deactivation of δ subunit-containing receptors suggest that propofol enhancement of both phasic and tonic inhibition may contribute to its anesthetic effect in the brain.