Počet záznamů: 1
Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms
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SYSNO ASEP 0546480 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms Tvůrce(i) 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, SAIZdroj.dok. British Journal of Pharmacology. - : Wiley - ISSN 0007-1188
Roč. 178, č. 19 (2021), s. 3888-3904Poč.str. 17 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova glutamate ; Munc13-1 ; neurosteroid ; phorbol ester ; pregnanolone ; presynaptic Vědní obor RIV FH - Neurologie, neurochirurgie, neurovědy Obor OECD Neurosciences (including psychophysiology CEP EF16_025/0007444 GA MZd - Ministerstvo zdravotnictví GJ16-03913Y GA ČR - Grantová agentura ČR TN01000013 GA TA ČR - Technologická agentura ČR LQ1604 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963 UT WOS 000664342800001 EID SCOPUS 85108298319 DOI 10.1111/bph.15529 Anotace 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. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2022 Elektronická adresa https://doi.org/10.1111/bph.15529
Počet záznamů: 1