Central GABA(A) receptors mediate GABAergic phasic and tonic inhibition. While synaptic alpha beta gamma GABA(A) receptors primarily mediate phasic inhibition, extrasynaptic alpha beta delta receptors play an important role in mediating tonic inhibition. Etomidate is a general anesthetic that produces its effects by enhancing GABA(A) receptor activity. We previously showed that etomidate modulates the gating of oocyte-expressed alpha beta gamma and alpha beta delta receptors with similar overall allosteric impact, but different pharmacological patterns. In alpha beta gamma receptors, etomidate enhances apparent GABA sensitivity (reduces GABA EC50), modestly increases maximal GABA efficacy, and slows current deactivation without affecting desensitization (Zhong et al., 2008). In alpha beta delta receptors characterized by low GABA efficacy, etomidate dramatically increases responses to both low and maximal GABA. The effects of etomidate on desensitization and deactivation of alpha beta delta receptors are unknown. To investigate the kinetic effects of etomidate on alpha 1 beta 3 delta receptors of defined subunit arrangement, we expressed concatenated trimer (beta 3-alpha 1-delta) and dimer (beta 3-alpha 1) GABA(A) receptor subunit assemblies in human embryonic kidney (HEK)293T cells and recorded whole-cell voltage-clamp currents during rapid external solution exchanges. As expected, etomidate substantially increased maximal GABA-induced currents and prolonged deactivation. Moreover, desensitization was significantly decreased by etomidate. During prolonged GABA applications, etomidate enhanced steady-state currents more than peak currents. Thus, etomidate enhances tonic GABAergic inhibition through extrasynaptic alpha beta delta receptors by both augmenting gating and reducing desensitization. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.