Cholesterol as a modulator of cannabinoid receptor CB2 signaling

Abstract 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 CB2, we demonstrate that cholesterol increases basal activation levels of the receptor and alters...

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Autores principales:	Alexei Yeliseev, Malliga R. Iyer, Thomas T. Joseph, Nathan J. Coffey, Resat Cinar, Lioudmila Zoubak, George Kunos, Klaus Gawrisch
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f7405dfa40aa4301afa918bbd3f3c38d
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spelling	oai:doaj.org-article:f7405dfa40aa4301afa918bbd3f3c38d2021-12-02T14:27:02ZCholesterol as a modulator of cannabinoid receptor CB2 signaling10.1038/s41598-021-83245-62045-2322https://doaj.org/article/f7405dfa40aa4301afa918bbd3f3c38d2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83245-6https://doaj.org/toc/2045-2322Abstract 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 CB2, 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 CB2 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 CB2 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.Alexei YeliseevMalliga R. IyerThomas T. JosephNathan J. CoffeyResat CinarLioudmila ZoubakGeorge KunosKlaus GawrischNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexei Yeliseev Malliga R. Iyer Thomas T. Joseph Nathan J. Coffey Resat Cinar Lioudmila Zoubak George Kunos Klaus Gawrisch Cholesterol as a modulator of cannabinoid receptor CB2 signaling
description	Abstract 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 CB2, 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 CB2 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 CB2 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.
format	article
author	Alexei Yeliseev Malliga R. Iyer Thomas T. Joseph Nathan J. Coffey Resat Cinar Lioudmila Zoubak George Kunos Klaus Gawrisch
author_facet	Alexei Yeliseev Malliga R. Iyer Thomas T. Joseph Nathan J. Coffey Resat Cinar Lioudmila Zoubak George Kunos Klaus Gawrisch
author_sort	Alexei Yeliseev
title	Cholesterol as a modulator of cannabinoid receptor CB2 signaling
title_short	Cholesterol as a modulator of cannabinoid receptor CB2 signaling
title_full	Cholesterol as a modulator of cannabinoid receptor CB2 signaling
title_fullStr	Cholesterol as a modulator of cannabinoid receptor CB2 signaling
title_full_unstemmed	Cholesterol as a modulator of cannabinoid receptor CB2 signaling
title_sort	cholesterol as a modulator of cannabinoid receptor cb2 signaling
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f7405dfa40aa4301afa918bbd3f3c38d
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Cholesterol as a modulator of cannabinoid receptor CB2 signaling

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