Cholesterol as a modulator of cannabinoid receptor CB 2 signaling.

Autor: Yeliseev A; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA. yeliseeva@mail.nih.gov., Iyer MR; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA. malliga.iyer@nih.gov., Joseph TT; Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Coffey NJ; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA., Cinar R; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA., Zoubak L; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA., Kunos G; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA., Gawrisch K; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Feb 12; Vol. 11 (1), pp. 3706. Date of Electronic Publication: 2021 Feb 12.
DOI: 10.1038/s41598-021-83245-6
Abstrakt: 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(2H)-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.
Databáze: MEDLINE
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