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Int. J. Mol. Sci. 2019, 20(8), 1837;

Structural Insights into CB1 Receptor Biased Signaling

Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science & Technology, P.O.BOX 3030, Irbid 22110, Jordan
Departamento de Química-Física Biológica, Instituto de Química Física Rocasolano (IQFR-CSIC), Serrano 119, 28006 Madrid, Spain
Chemistry and Biochemistry Department, UNC Greensboro, Greensboro, NC 27412, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work
Received: 5 March 2019 / Revised: 9 April 2019 / Accepted: 11 April 2019 / Published: 13 April 2019
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
PDF [1014 KB, uploaded 13 April 2019]


The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.
Keywords: CB1 receptor; biased signaling; functional selectivity; cannabinoids CB1 receptor; biased signaling; functional selectivity; cannabinoids
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Al-Zoubi, R.; Morales, P.; Reggio, P.H. Structural Insights into CB1 Receptor Biased Signaling. Int. J. Mol. Sci. 2019, 20, 1837.

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Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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