RT Journal Article
SR Electronic
T1 The Sulfated Steroids Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate Inhibit the <em>α</em>1<em>β</em>3<em>γ</em>2L GABA<sub>A</sub> Receptor by Stabilizing a Novel Nonconducting State
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 68
OP 77
DO 10.1124/molpharm.121.000385
VO 101
IS 2
A1 Spencer R. Pierce
A1 Allison L. Germann
A1 Joe Henry Steinbach
A1 Gustav Akk
YR 2022
UL http://molpharm.aspetjournals.org/content/101/2/68.abstract
AB The GABAA receptor is inhibited by the endogenous sulfated steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS). It has been proposed in previous work that these steroids act by enhancing desensitization of the receptor. Here, we have investigated the modulatory effects of the steroids on the human α1β3γ2L GABAA receptor. Using electrophysiology and quantitative model-based data analysis, we show that exposure to the steroid promotes occupancy of a nonconducting state that retains high affinity to the transmitter but whose properties differ from those of the classic, transmitter-induced desensitized state. From the analysis of the inhibitory actions of two combined steroids, we infer that PS and DHEAS act through shared or overlapping binding sites.SIGNIFICANCE STATEMENT Previous work has proposed that sulfated neurosteroids inhibit the GABAA receptor by enhancing the rate of entry into the desensitized state. This study shows that the inhibitory steroids pregnenolone sulfate and dehydroepiandrosterone sulfate act through a common interaction site by stabilizing a distinct nonconducting state.