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Corticosteroids as Selective and Effective Modulators of Glycine Receptors
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SYSNO ASEP 0575132 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Corticosteroids as Selective and Effective Modulators of Glycine Receptors Author(s) Solntseva, E. I. (RU)
Bukanova, J. V. (RU)
Kondratenko, R. (RU)
Kudová, Eva (UOCHB-X) RID, ORCIDSource Title ACS Chemical Neuroscience. - : American Chemical Society - ISSN 1948-7193
Roč. 14, č. 17 (2023), s. 3132-3142Number of pages 11 s. Language eng - English Country US - United States Keywords GABAA receptor ; glycine receptor ; corticosteroids ; structure-activity relationship study OECD category Neurosciences (including psychophysiology R&D Projects LX22NPO5104 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 001049417000001 EID SCOPUS 85169054920 DOI https://doi.org/10.1021/acschemneuro.3c00287 Annotation The mechanism of the negative impact of corticosteroids on the induction and progress of mental illness remains unclear. In this work, we studied the effects of corticosteroids on the activity of neuronal glycine receptors (GlyR) and GABA-A receptors (GABAAR) by measuring the chloride current induced by the application of GABA (2 or 5 μM) to isolated cerebellar Purkinje cells (IGABA) and by the application of glycine (100 μM) to pyramidal neurons of the rat hippocampus (IGly). It was found that corticosterone, 5α-dihydrodeoxycorticosterone, allotetrahydrocorticosterone, cortisol, and 17α,21-dihydroxypregnenolone were able to accelerate the desensitization of the IGly at physiological concentrations (IC50 values varying from 0.39 to 0.72 μM). Next, cortisone, 11-deoxycortisol, 11-deoxycorticosterone, 5β-dihydrodeoxycorticosterone, and tetrahydrocorticosterone accelerated the desensitization of IGly with IC50 values varying from 10.3 to 15.2 μM. Allotetrahydrocorticosterone and tetrahydrocorticosterone potentiated the IGABA albeit with high EC50 values (18–23 μM). The rest of the steroids had no effect on IGABA in the range of concentrations of 1–100 μM. Finally, our study has suggested a structural relationship of the 3β-hydroxyl group/3-oxo group with the selective modulatory activity on GlyRs in contrast to the 3α-hydroxyl group that is pivotal for GABAARs. In summary, our results suggest that increased GlyR desensitization by corticosteroids may contribute to brain dysfunction under chronic stress and identify corticosteroids for further development as selective modulators of GlyRs. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1021/acschemneuro.3c00287
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