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.