Abstract
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.
Footnotes
- Received August 4, 2021.
- Accepted November 21, 2021.
This work was supported by National Institutes of Health National Institute of General Medical Sciences [Grants R01GM108580, R35GM140947] and funds from the Taylor Family Institute for Innovative Psychiatric Research.
No author has an actual or perceived conflict of interest with the contents of this article.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Inhibition of GABAAR by Sulfated Steroids
