AI Article Synopsis
- The endogenous sulfated steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS) inhibit the GABA receptor by enhancing desensitization.
- Using electrophysiology and data analysis, the study reveals that these steroids promote a nonconducting state of the receptor that has high affinity for the transmitter but behaves differently from the classic desensitized state.
- The findings suggest that PS and DHEAS interact with the GABA receptor through shared or overlapping binding sites.
Article Abstract
The GABA 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 132L GABA 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 GABA 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969134 | PMC |
| http://dx.doi.org/10.1124/molpharm.121.000385 | DOI Listing |
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