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Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors
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SYSNO ASEP 0546864 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors Author(s) Dolejší, Eva (FGU-C) RID, ORCID
Chetverikov, Nikolai (FGU-C) RID, ORCID, SAI
Szánti-Pintér, Eszter (UOCHB-X) ORCID
Nelic, Dominik (FGU-C) ORCID, RID
Randáková, Alena (FGU-C) RID, ORCID
Doležal, Vladimír (FGU-C) RID, ORCID
El-Fakahany, E. E. (US)
Kudová, Eva (UOCHB-X) RID, ORCID
Jakubík, Jan (FGU-C) RID, ORCIDArticle number 114699 Source Title Biochemical Pharmacology. - : Elsevier - ISSN 0006-2952
Roč. 192, Oct (2021)Number of pages 12 s. Language eng - English Country US - United States Keywords neuroactive steroids ; cholesterol ; muscarinic receptors ; allosteric modulation Subject RIV ED - Physiology OECD category Physiology (including cytology) R&D Projects GA19-05318S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963 UT WOS 000701938400005 EID SCOPUS 85111566505 DOI 10.1016/j.bcp.2021.114699 Annotation Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 mu M. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcumnium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane. 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/10.1016/j.bcp.2021.114699
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