ACTIONS OF THE GENERAL ANESTHETIC PROPOFOL ON RECOMBINANT HUMAN GABA(A) RECEPTORS - INFLUENCE OF RECEPTOR SUBUNITS

The intravenous general anesthetic 2,6-diisopropylphenol (propofol) po tentiates GABA(A) receptor function, but the precise mechanisms and sp ecificity of this action are still unclear. To study the influence of receptor subunit composition on the action of propofol, 18 different c ombinations of cloned cDNAs coding for human brain subunit isoforms of the GABA(A) receptor, as well as mRNAs from mouse brain, were express ed in Xenopus oocytes, and effects of this anesthetic were investigate d by the voltage-clamp technique. We found that low concentrations (1- 10 mu M) Of propofol dramatically potentiated GABA-evoked Cl- currents in all GABA(A) receptor constructs tested. This action did not requir e specific subunits but was correlated inversely with the GABA sensiti vity of each receptor construct. Larger concentrations (10-25 mu M) Of propofol produced direct activation of Cl- currents, and this action was dependent on the expression of the beta-subunit of the GABA(A) rec eptor and did not correlate with the GABA sensitivity of the receptors . These results suggest that propofol exerts a dual effect on GABA(A) receptors: a positive modulation of the GABA-mediated action on GABA(A ) receptors that is not influenced by the receptor subunit composition , and a specific interaction with the beta-subunit that directly activ ates the GABA(A) receptor-coupled Cl- channel.