Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant α4β3δ and α4β3 GABAA 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 GABAA receptors (GABAARs), particularly highly GABA-sensitive extrasynaptic receptor subtypes that give rise to sustained inhibitory currents, are uniquely sensitive to GABAAR-active anesthetics. A prominent population of extrasynaptic GABAARs is made up of α4, β2 or β3, and δ subunits. Considering the demonstrated importance of GABA receptor β3 subunits for in vivo anesthetic effects of etomidate and propofol, we decided to investigate the effects of GABA anesthetics on “extrasynaptic” α4β3δ and also binary α4β3 receptors expressed in human embryonic kidney (HEK) cells. Consistent with previous work on similar receptor subtypes we show that maximal GABA currents through “extrasynaptic” α4β3δ receptors, receptors defined by sensitivity to EtOH (30 mM) and the β-carboline β-CCE (1 μM), are enhanced by the GABAAR-active anesthetics etomidate, propofol, and the neurosteroid anesthetic THDOC. Furthermore, we show that receptors formed by α4β3 subunits alone also show high GABA sensitivity and that saturating GABA responses of α4β3 receptors are increased to the same extent by etomidate, propofol, and THDOC as are α4β3δ receptors. Therefore, both α4β3 and α4β3δ receptors show low GABA efficacy, and GABA is also a partial agonist on certain binary αβ receptor subtypes. Increasing GABA efficacy on α4/6β3δ and α4β3 receptors is likely to make an important contribution to the anesthetic effects of etomidate, propofol and the neurosteroid THDOC.