Neurosteroids and steroid hormones are allosteric modulators of muscarinic receptors
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34555368
DOI
10.1016/j.neuropharm.2021.108798
PII: S0028-3908(21)00353-1
Knihovny.cz E-resources
- Keywords
- Allosteric modulation, Muscarinic receptor, Neurosteroid, Steroid hormone,
- MeSH
- Acetylcholine metabolism MeSH
- Allosteric Regulation MeSH
- Adrenal Cortex Hormones metabolism MeSH
- Corticosterone metabolism MeSH
- Cricetinae MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Neurosteroids metabolism MeSH
- Gonadal Steroid Hormones metabolism MeSH
- Progesterone metabolism MeSH
- Receptors, Muscarinic metabolism MeSH
- Animals MeSH
- Check Tag
- Cricetinae MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholine MeSH
- Adrenal Cortex Hormones MeSH
- Corticosterone MeSH
- Neurosteroids MeSH
- Gonadal Steroid Hormones MeSH
- Progesterone MeSH
- Receptors, Muscarinic MeSH
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.
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
Institute of Physiology Czech Academy of Sciences Prague Czech Republic
References provided by Crossref.org
Muscarinic Receptors in Cardioprotection and Vascular Tone Regulation
Allosteric Modulation of Muscarinic Receptors by Cholesterol, Neurosteroids and Neuroactive Steroids
Allosteric Modulation of GPCRs of Class A by Cholesterol
