Etomidate Effects on Desensitization and Deactivation of 43 GABA Receptors Inducibly Expressed in HEK293 TetR Cells.

Central 4 receptors are the most abundant isoform of subunit-containing extrasynaptic GABA receptors that mediate tonic inhibition. Although the amplitude of GABA-activated currents through 4 receptors is modulated by multiple general anesthetics, the effects of general anesthetics on desensitization and deactivation of 4 receptors remain unknown. In the current study, we investigated the effect of etomidate, a potent general anesthetic, on the kinetics and the pseudo steady-state current amplitude of 43 receptors inducibly expressed in human embryonic kidney 293 TetR cells. Etomidate directly activates 43 receptors in a concentration-dependent manner. Etomidate at a clinically relevant concentration (3.2 M) enhances maximal response without altering the EC of GABA concentration response. Etomidate also increases the extent of desensitization and prolongs the deactivation of 43 receptors in the presence of maximally activating concentrations of GABA (1 mM). To mimic the modulatory effect of etomidate on tonic currents, long pulses (30-60 seconds) of a low GABA concentration (1 M) were applied to activate 43 receptors in the absence and presence of etomidate. Although etomidate increases the desensitization of 43 receptors, the pseudo steady-state current amplitude at 1 M GABA is augmented by etomidate. Our data demonstrate that etomidate enhances the pseudo steady-state current of 43 receptors evoked by a GABA concentration comparable to an ambient GABA level, suggesting that 43 receptors may mediate etomidate's anesthetic effect in the brain.