Journal
NEUROPHARMACOLOGY
Volume 199, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2021.108798
Keywords
Neurosteroid; Steroid hormone; Allosteric modulation; Muscarinic receptor
Categories
Funding
- Czech Academy of Sciences [RVO:67,985,823, RVO:61388963]
- Programs of Strategy AV21
- Grant Agency of the Czech Republic grant [19-05318S]
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The study revealed that membrane cholesterol can modulate the function of muscarinic receptors, with different steroidal compounds showing varying affinity for the receptors. Corticosterone and progesterone were found to allosterically modulate receptor function under physiological conditions.
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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