The Sulfated Steroids Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate Inhibit the α 1 β 3 γ 2L GABA A Receptor by Stabilizing a Novel Nonconducting State

• Published in: Molecular pharmacology Vol. 101; no. 2; pp. 68 - 77
• Main Authors: Pierce, Spencer R, Germann, Allison L, Steinbach, Joe Henry, Akk, Gustav
• Format: Journal Article
• Language: English
• Published: United States 01-02-2022
• Subjects: Animals; Dehydroepiandrosterone Sulfate - chemistry; Dehydroepiandrosterone Sulfate - pharmacology; Dose-Response Relationship, Drug; Female; GABA Antagonists - chemistry; GABA Antagonists - pharmacology; Humans; Neurosteroids - chemistry; Neurosteroids - pharmacology; Pregnenolone - chemistry; Pregnenolone - pharmacology; Protein Stability; Receptors, GABA-A - chemistry; Receptors, GABA-A - metabolism; Xenopus laevis
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/molpharm.121.000385

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
1
3
2L 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.