Received for publication June 2, 2004.
Revised July 31, 2004.
Accepted for publication August 24, 2004.

MULTIPLE ACTIONS OF PROPOFOL ON AND GABA_A RECEPTORS

Abstract

GABA_A receptors are predominantly composed of and isoforms in the brain. It has been proposed that receptors mediate phasic inhibition while 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 and receptors are uncertain. We transfected human embryonic kidney (HEK293T) cells with cDNAs encoding rat 1, 6, 3, 2L or 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 132L and 632L receptors, but propofol increased those for 13 and 63 receptors differently, the increase being greater for 13 than for 63 receptors. Propofol (10 µM) produced similar alterations in 132L and 632L receptor currents when using a pre-application protocol; peak currents were not altered, desensitization was reduced, and deactivation was prolonged. Propofol enhanced peak currents for both 13 and 63 receptors, but the enhancement was greater for 13 receptors. Desensitization of these two isoforms was not modified by propofol. Propofol did not alter the deactivation rate of 13 receptor currents but did slow deactivation of 63 receptor currents. The findings that propofol reduced desensitization and prolonged deactivation of 2L subunit-containing receptors and enhanced peak currents or prolonged deactivation of subunit-containing receptors suggest that propofol enhancement of both phasic and tonic inhibition may contribute to its anesthetic effect in the brain.

Key words: GABAA, GABAC, Gases/general anesthetics

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