The Sulfated Steroids Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate Inhibit the α1β3γ2L GABA(A) Receptor by Stabilizing a Novel Nonconducting State
| Autor: | Gustav Akk, Spencer R. Pierce, Joseph H. Steinbach, Allison L. Germann |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Neuroactive steroid
medicine.medical_treatment Pharmacology Steroid GABA Antagonists chemistry.chemical_compound Xenopus laevis Dehydroepiandrosterone sulfate Sulfation Desensitization (telecommunications) medicine Animals Humans Receptor Dose-Response Relationship Drug GABAA receptor Dehydroepiandrosterone Sulfate Protein Stability Articles Receptors GABA-A chemistry Pregnenolone Molecular Medicine Female Pregnenolone sulfate Neurosteroids |
| Zdroj: | Mol Pharmacol |
| Popis: | The γ-aminobutyric acid type A (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 non-conducting 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. We show here that the inhibitory steroids pregnenolone sulfate and dehydroepiandrosterone sulfate act through a common interaction site by stabilizing a distinct non-conducting state. |
| Databáze: | OpenAIRE |
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