The Sulfated Steroids Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate Inhibit the α1β3γ2L GABAA Receptor by Stabilizing a Novel Nonconducting State

The GABA(A) receptor is inhibited by the endogenous sulfated steroids pregnenolone sulfate (PS) and dehydroepiandroster-one 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 a1b3c2L GABA(A) receptor. Using electrophysiology and quantitative model-based data analy-sis, we show that exposure to the steroid promotes occu-pancy of a nonconducting state that retains high affinity to the transmitter but whose properties differ from those of the clas-sic, 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 GABA(A) 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 non-conducting state.

Automated summary

This study demonstrates that inhibitory steroids pregnenolone sulfate and dehydroepiandrosterone sulfate act through a common interaction site by stabilizing a distinct non-conducting state.