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Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms

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, SAI}
Source Title	British Journal of Pharmacology. - : Wiley - ISSN 0007-1188 Roč. 178, č. 19 (2021), s. 3888-3904
Number 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	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

Number of the records: 1