National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Sci Rep. 2021 Feb 12;11(1):3706. doi: 10.1038/s41598-021-83245-6.
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, 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 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 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.
通过整联膜 G 蛋白偶联受体 (GPCR) 的信号转导受细胞膜脂质组成的影响。通过使用新型高亲和力的人类大麻素受体 CB 的配体，我们证明胆固醇增加了受体的基础激活水平，并改变了这些配体的药理学分类。我们的结果表明，（2-（6-氯-2-（（2,2,3,3-四甲基环丙烷-1-羰基）亚氨基）苯并[d]噻唑-3(2H)-基）乙酯配体 (MRI-2646) 在没有胆固醇的膜中作为 CB 的部分激动剂，而在含有胆固醇的膜中作为中性拮抗剂或部分反向激动剂。特定配体对不同类型膜中 CB 激活的差异影响可能对筛选 GPCR 活性调节剂的药物候选物具有重要意义。MD 模拟表明，胆固醇对与 G 蛋白复合物相互作用的受体的细胞内区域施加变构效应，从而改变 G 蛋白的募集。
