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Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms
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SYSNO ASEP 0546480 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms Author(s) Smejkalová, Tereza (FGU-C) RID, ORCID
Kořínek, Miloslav (FGU-C) RID, ORCID
Krůšek, Jan (FGU-C) RID, ORCID
Hrčka Krausová, Barbora (FGU-C) ORCID, RID
Candelas Serra, Miriam (FGU-C) ORCID, RID
Hajduković, Dragana (FGU-C)
Kudová, Eva (UOCHB-X) RID, ORCID
Chodounská, Hana (UOCHB-X) RID, ORCID
Vyklický ml., Ladislav (FGU-C) RID, ORCID, SAISource Title British Journal of Pharmacology. - : Wiley - ISSN 0007-1188
Roč. 178, č. 19 (2021), s. 3888-3904Number of pages 17 s. Language eng - English Country GB - United Kingdom Keywords glutamate ; Munc13-1 ; neurosteroid ; phorbol ester ; pregnanolone ; presynaptic Subject RIV FH - Neurology OECD category Neurosciences (including psychophysiology R&D Projects EF16_025/0007444 GA MZd - Ministry of Health (MZ) GJ16-03913Y GA ČR - Czech Science Foundation (CSF) TN01000013 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963 UT WOS 000664342800001 EID SCOPUS 85108298319 DOI https://doi.org/10.1111/bph.15529 Annotation Background and Purpose:Neurosteroids influence neuronal function and have multiple promising clinical applications. Direct modulation of postsynaptic neurotransmitter receptors by neurosteroids is well characterized, but presynaptic effects remain poorly understood. Here, we report presynaptic glutamate release potentiation by neurosteroids pregnanolone and pregnanolone sulfate and compare their mechanisms of action to phorbol 12,13-dibutyrate (PDBu), a mimic of the second messenger DAG.Experimental Approach:We use whole-cell patch-clamp electrophysiology and pharmacology in rat hippocampal microisland cultures and total internal reflection fluorescence (TIRF) microscopy in HEK293 cells expressing GFP-tagged vesicle priming protein Munc13-1, to explore the mechanisms of neurosteroid presynaptic modulation.Key Results:Pregnanolone sulfate and pregnanolone potentiate glutamate release downstream of presynaptic Ca2+ influx, resembling the action of a phorbol ester PDBu. PDBu partially occludes the effect of pregnanolone, but not of pregnanolone sulfate. Calphostin C, an inhibitor that disrupts DAG binding to its targets, reduces the effect PDBu and pregnanolone, but not of pregnanolone sulfate, suggesting that pregnanolone might interact with a well-known DAG/phorbol ester target Munc13-1. However, TIRF microscopy experiments found no evidence of pregnanolone-induced membrane translocation of GFP-tagged Munc13-1, suggesting that pregnanolone may regulate Munc13-1 indirectly or interact with other DAG targets.Conclusion and Implications:We describe a novel presynaptic effect of neurosteroids pregnanolone and pregnanolone sulfate to potentiate glutamate release downstream of presynaptic Ca2+ influx. The mechanism of action of pregnanolone, but not of pregnanolone sulfate, partly overlaps with that of PDBu. Presynaptic effects of neurosteroids may contribute to their therapeutic potential in the treatment of disorders of the glutamate system. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2022 Electronic address https://doi.org/10.1111/bph.15529
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