Neurosteroids and steroid hormones are allosteric modulators of muscarinic receptors

• Published in: Neuropharmacology Vol. 199; p. 108798
• Main Authors: Dolejší, Eva, Szánti-Pintér, Eszter, Chetverikov, Nikolai, Nelic, Dominik, Randáková, Alena, Doležal, Vladimír, Kudová, Eva, Jakubík, Jan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2021
• Subjects: Acetylcholine - metabolism; Adrenal Cortex Hormones - metabolism; Allosteric modulation; Allosteric Regulation; Animals; Cells, Cultured; Corticosterone - metabolism; Cricetinae; Gonadal Steroid Hormones - metabolism; Humans; Muscarinic receptor; Neurosteroid; Neurosteroids - metabolism; Progesterone - metabolism; Receptors, Muscarinic - metabolism; Steroid hormone; Neurosteroid; Muscarinic receptor; Allosteric modulation; Steroid hormone
• ISSN: 0028-3908; 1873-7064
• DOI: 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.
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•Some neurosteroids and steroid hormones bind to muscarinic acetylcholine receptors with the affinity of 100 nM or greater.•Steroids acting at nanomolar concentrations represent the novel pharmacophore of muscarinic allosteric modulators.•Corticosterone and progesterone allosterically modulate muscarinic receptors at physiologically relevant concentrations.