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Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations

SYSNO ASEP	0558978
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations
Author(s)	Kysilov, Bohdan (FGU-C)_{ORCID, SAI} Hrčka Krausová, Barbora (FGU-C)_{ORCID, RID} Vyklický, Vojtěch (FGU-C)_{RID, ORCID, SAI} Smejkalová, Tereza (FGU-C)_{RID, ORCID} Kořínek, Miloslav (FGU-C)_{RID, ORCID} Horák, Martin (FGU-C)_{RID, ORCID} Chodounská, Hana (UOCHB-X)_{RID, ORCID} Kudová, Eva (UOCHB-X)_{RID, ORCID} Černý, Jiří (FGU-C)_{RID, ORCID} Vyklický ml., Ladislav (FGU-C)_{RID, ORCID, SAI}
Source Title	British Journal of Pharmacology. - : Wiley - ISSN 0007-1188 Roč. 179, č. 15 (2022), s. 3970-3990
Number of pages	21 s.
Language	eng - English
Country	GB - United Kingdom
Keywords	GRIN channelopathy ; NMDA receptor ; positive allosteric modulator ; steroids ; transmembrane domain
OECD category	Neurosciences (including psychophysiology
R&D Projects	GA20-17945S GA ČR - Czech Science Foundation (CSF)
	EF16_025/0007444 GA MZd - Ministry of Health (MZ)
	TN01000013 GA TA ČR - Technology Agency of the Czech Republic (TA ČR)
Method of publishing	Open access
Institutional support	FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963
UT WOS	000779296100001
EID SCOPUS	85127541114
DOI	10.1111/bph.15841
Annotation	Background and Purpose N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function. Experimental Approach We have used whole-cell patch-clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone-based NMDAR modulators. Key Results Analysis of the action of 4-(20-oxo-5 beta-pregnan-3 beta-yl) butanoic acid (EPA-But) at the NMDAR indicates that the effect of this steroid with a “bent” structure is different from that of cholesterol and oxysterols and shares a disuse-dependent mechanism of NMDAR potentiation with the “planar” steroid 20-oxo-pregn-5-en-3 beta-yl sulfate (PE-S). The potentiating effects of EPA-But and PE-S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA-But. No correlation was found between the effects of EPA-But and PE-S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder. Conclusion and Implications Our results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with glutamatergic system hypofunction.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2023
Electronic address	https://doi.org/10.1111/bph.15841

Number of the records: 1