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The gamma-aminobutyric acid (GABA)A receptor/chloride channel has a broad-spectrum anesthetic sensitivity and is a key regulator of arousal. Each receptor/channel complex is an assembly of five protein subunits. Six subunit classes have been identified, each containing one to six members; many combinations are expressed throughout the brain. Benzodiazepines and intravenous anesthetic agents are clearly subunit dependent, but the literature to date suggests that volatile anesthetics are not. The physiological role of the delta subunit remains enigmatic, and it has not been examined as a determinant of anesthetic sensitivity.Combinations of GABAA receptor subunit cDNAs were injected into Xenopus laevis oocytes: alpha1 beta1, alpha1 beta1 gamma2L, alpha1 beta1 delta, and alpha1 beta1 gamma2L delta. Expression of functional ion channels with distinct signalling and pharmacologic properties was demonstrated within 1–4 days by established electrophysiological methods.Co-expression of the delta subunit produced changes in receptor affinity; current density; and the modulatory efficacy of diazepam, zinc, and lanthanum; it also produced subtle changes in the rate of desensitization in response to GABA. Isoflurane enhanced GABA-induced responses from all combinations: alpha beta delta (> 10-fold) > alpha beta > alpha beta gamma >or= to alpha beta gamma delta ([nearly =] 5-fold). Dose-response plots were bell shaped. Compared with alpha beta gamma receptors (EC50 = 225 micro Meter), both alpha beta delta (EC50 = 372 micro Meter) and alpha beta gamma delta (EC sub 50 = 399 micro Meter) had a reduced affinity for isoflurane. Isoflurane (at a concentration close to the EC50 for each subunit) increased the affinity of GABA for its receptor but depressed the maximal response (alpha beta gamma and alpha beta gamma delta). In contrast, the small currents through alpha beta delta receptors were enhanced, even at saturating agonist concentrations.delta Subunit expression alters GABAA receptor function but is not an absolute determinant of anesthetic sensitivity.