Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors

Eva Dolejší, Nikolai Chetverikov, Eszter Szánti-Pintér, Dominik Nelic, Alena Randáková, Vladimír Doležal, Esam E. El-Fakahany, Eva Kudová, Jan Jakubík

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 µM. 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 alcuronium 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.

Original languageEnglish (US)
Article number114699
JournalBiochemical Pharmacology
Volume192
Early online dateJul 26 2021
DOIs
StatePublished - Oct 2021

Bibliographical note

Funding Information:
This research was funded by the Czech Academy of Sciences institutional support [RVO: 67985823 ] (ED, NC, DN, AR, VD and JJ) and [RVO:61388963], Programs of Strategy AV21 (ES-P and EK) and the Grant Agency of the Czech Republic grant [19-05318S].

Publisher Copyright:
© 2021 The Authors

Keywords

  • Allosteric modulation
  • Cholesterol
  • Muscarinic receptors
  • Neuroactive steroids

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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