Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline
Language English Country England, Great Britain Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29407765
DOI
10.1016/j.neuropharm.2018.01.027
PII: S0028-3908(18)30027-3
Knihovny.cz E-resources
- Keywords
- Cholesterol (PubChem CID: 5997), Membrane cholesterol, Methyl beta-cyclodextrin (PubChem CID: 51051622), Molecular dynamics, Muscarinic acetylcholine receptors, N-methyl scopolamine (PubChem CID: 5459110), Receptor activation, Xanomeline, Xanomeline (Pubchem CID: 60809),
- MeSH
- Muscarinic Agonists pharmacokinetics MeSH
- Cell Membrane drug effects metabolism MeSH
- CHO Cells cytology MeSH
- Cholesterol metabolism MeSH
- Cricetulus MeSH
- Inositol Phosphates metabolism MeSH
- Magnetic Resonance Spectroscopy MeSH
- Models, Molecular MeSH
- Flow Cytometry MeSH
- Pyridines pharmacokinetics MeSH
- Radioligand Assay MeSH
- Receptors, Muscarinic genetics metabolism MeSH
- Molecular Docking Simulation MeSH
- Thiadiazoles pharmacokinetics MeSH
- Tritium pharmacokinetics MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Muscarinic Agonists MeSH
- Cholesterol MeSH
- Inositol Phosphates MeSH
- Pyridines MeSH
- Receptors, Muscarinic MeSH
- Thiadiazoles MeSH
- Tritium MeSH
- Calcium MeSH
- xanomeline MeSH Browser
Xanomeline (3-(Hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole) is a muscarinic agonist that is considered to be functionally selective for the M1/M4 receptor subtypes. Part of xanomeline binding is resistant to washing. Wash-resistant xanomeline activates muscarinic receptors persistently, except for the M5 subtype. Mutation of leucine 6.46 to isoleucine at M1 or M4 receptors abolished persistent activation by wash-resistant xanomeline. Reciprocal mutation of isoleucine 6.46 to leucine at the M5 receptor made it sensitive to activation by wash-resistant xanomeline. Lowering of membrane cholesterol made M1 and M4 mutants and M5 wild type receptors sensitive to activation by wash-resistant xanomeline. Molecular docking revealed a cholesterol binding site in the groove between transmembrane helices 6 and 7. Molecular dynamics showed that interaction of cholesterol with this binding site attenuates receptor activation. We hypothesize that differences in cholesterol binding to this site between muscarinic receptor subtypes may constitute the basis for xanomeline apparent functional selectivity and may have notable therapeutic implications. Differences in receptor-membrane interactions, rather than in agonist-receptor interactions, represent a novel possibility to achieve pharmacological selectivity. Our findings may be applicable to other G protein coupled receptors.
References provided by Crossref.org
Agonist-selective activation of individual G-proteins by muscarinic receptors
Allosteric Modulation of Muscarinic Receptors by Cholesterol, Neurosteroids and Neuroactive Steroids
Allosteric Modulation of GPCRs of Class A by Cholesterol
Novel M2 -selective, Gi -biased agonists of muscarinic acetylcholine receptors
Current Advances in Allosteric Modulation of Muscarinic Receptors
