MOLECULAR DETERMINANTS OF GENERAL ANESTHETIC ACTION - ROLE OF GABA-A RECEPTOR STRUCTURE

Using receptors expressed from mouse brain mRNA in Xenopus oocytes, we found that enhancement of type A gamma-aminobutyric acid (GABA(A)) receptor-gated Cl-channel response is a common action of structurally diverse anesthetics, suggesting that the GABA(A) receptor plays an important role in anesthesia. To determine if GABA(A) receptor subunit composition influences actions of anesthetics, we expressed subunit cRNAs in Xenopus oocytes and measured effects of enflurane on GABA-activated Cl-currents. Potentiation of GABA-activated currents by enflurane was dependent on the.composition of GABA(A) receptor protein subunits; the order of sensitivity was alpha1beta1 > alpha1beta1gamma2s = alpha1beta1gamma2L> total mRNA. The results suggest that anesthetics with simple structures may act on the GABA(A) receptor protein complex to modulate the Cl- channel activity and provide a molecular explanation for the synergistic clinical interactions between benzodiazepines and general anesthetics.