Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha 4 beta 3 delta and alpha 4 beta 3 GABA(A) receptors expressed in HEK cells

General anesthetics, once thought to exert their effects through non-specific membrane effects, have highly specific ion channel targets that can silence neuronal populations in the nervous system, thereby causing unconsciousness and immobility, characteristic of general anesthesia. Inhibitory GABA(A) receptors (GABA(A)Rs), particularly highly GABA-sensitive extrasynaptic receptor subtypes that give rise to sustained inhibitory currents, are uniquely sensitive to GABA(A)R-active anesthetics. A prominent population of extrasynaptic GABA(A)Rs is made up of alpha 4, beta 2 or beta 3, and delta subunits. Considering the demonstrated importance of GABA receptor beta 3 subunits for in vivo anesthetic effects of etomidate and propofol, we decided to investigate the effects of GABA anesthetics on extrasynaptic alpha 4 beta 3 delta and also binary alpha 4 beta 3 receptors expressed in human embryonic kidney (HEK) cells. Consistent with previous work on similar receptor subtypes we show that maximal GABA currents through extrasynaptic alpha 4 beta 3 delta receptors, receptors defined by sensitivity to EtOH (30 mM) and the beta-carboline beta-CCE (1 mu M), are enhanced by the GABA(A)R-active anesthetics etomidate, propofol, and the neurosteroid anesthetic THDOC. Furthermore, we show that receptors formed by alpha 4 beta 3 subunits alone also show high GABA sensitivity and that saturating GABA responses of alpha 4 beta 3 receptors are increased to the same extent by etomidate, propofol, and THDOC as are alpha 4 beta 3 delta receptors. Therefore, both alpha 4 beta 3 and alpha 4 beta 3 delta receptors show low GABA efficacy, and GABA is also a partial agonist on certain binary alpha beta receptor subtypes. Increasing GABA efficacy on alpha 4/6 beta 3 delta and alpha 4 beta 3 receptors is likely to make an important contribution to the anesthetic effects of etomidate, propofol and the neurosteroid THDOC. (C) 2008 Elsevier Ltd. All rights reserved.