New Insights in Cannabinoid Receptor Structure and Signaling

Abstract

Background: Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic target for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within the mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.

Conclusion: In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.

Keywords: Cannabinoid receptor; allosteric ligand; biased signaling; mitochondria; orphan GPCRs; structure..

Fig. (1)

Schematic model of CB1 and CB2, showing the terminal tails, TM helices, intracellular loops, as well as the major intracellular signaling pathways.

Fig. (2)

Schematic representation of biased signaling at CB1. Structurally different ligands will induce diverse conformations of the receptor, which may then favor one of the possible signaling pathways over others. In this diagram, the unbiased agonist CP55,940 engages the CB1 and activates both G protein- and β-arrestin-dependent signaling pathways. PNR-4-20 is biased toward the activation of the Gαi heterotrimer over β-arrestin, while ORG27569 favorably activates β-arrestin.