Neurosteroids and steroid hormones are allosteric modulators of muscarinic receptor

0546861 - FGÚ 2022 RIV NL eng J - Journal Article
Dolejší, Eva - Szánti-Pintér, Eszter - Chetverikov, Nikolai - Nelic, Dominik - Randáková, Alena - Doležal, Vladimír - Kudová, Eva - Jakubík, Jan
Neurosteroids and steroid hormones are allosteric modulators of muscarinic receptor.
Neuropharmacology. Roč. 199, Nov 1 (2021), č. článku 108798. ISSN 0028-3908. E-ISSN 1873-7064
R&D Projects: GA ČR(CZ) GA19-05318S
Grant - others:AV ČR(CZ) StrategieAV21/10
Program: StrategieAV
Institutional support: RVO:67985823 ; RVO:61388963
Keywords : neurosteroid * steroid hormone * allosteric modulation * muscarinic receptor
OECD category: Physiology (including cytology); Physiology (including cytology) (UOCHB-X)
Impact factor: 5.273, year: 2021
Method of publishing: Open access
https://doi.org/10.1016/j.neuropharm.2021.108798

The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone and some neurosteroids bound to muscarinic receptors with the affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.
Permanent Link: http://hdl.handle.net/11104/0323238