Cholesterol as a modulator of cannabinoid receptor CB2 signaling

Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB 2 , we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pha...

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Veröffentlicht in:Scientific reports 2021-02, Vol.11 (1), p.3706-3706, Article 3706
Hauptverfasser: Yeliseev, Alexei, Iyer, Malliga R., Joseph, Thomas T., Coffey, Nathan J., Cinar, Resat, Zoubak, Lioudmila, Kunos, George, Gawrisch, Klaus
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Sprache:eng
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Zusammenfassung:Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB 2 , we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzo[ d ]thiazol-3(2 H )-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB 2 in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes. The differential effects of a specific ligand on activation of CB 2 in different types of membranes may have implications for screening of drug candidates in a search of modulators of GPCR activity. MD simulation suggests that cholesterol exerts an allosteric effect on the intracellular regions of the receptor that interact with the G-protein complex thereby altering the recruitment of G protein.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-83245-6