An Update on Non-CB₁, Non-CB₂ Cannabinoid Related G-Protein-Coupled Receptors

The endocannabinoid system (ECS) has been shown to be of great importance in the regulation of numerous physiological and pathological processes. To date, two Class A G-protein-coupled receptors (GPCRs) have been discovered and validated as the main therapeutic targets of this system: the cannabinoid receptor type 1 (CB₁), which is the most abundant neuromodulatory receptor in the brain, and the cannabinoid receptor type 2 (CB₂), predominantly found in the immune system among other organs and tissues. Endogenous cannabinoid receptor ligands (endocannabinoids) and the enzymes involved in their synthesis, cell uptake, and degradation have also been identified as part of the ECS. However, its complex pharmacology suggests that other GPCRs may also play physiologically relevant roles in this therapeutically promising system. In the last years, GPCRs such as GPR18 and GPR55 have emerged as possible missing members of the cannabinoid family. This categorization still stimulates strong debate due to the lack of pharmacological tools to validate it. Because of their close phylogenetic relationship, the Class A orphan GPCRs, GPR3, GPR6, and GPR12, have also been associated with the cannabinoids. Moreover, certain endo-, phyto-, and synthetic cannabinoid ligands have displayed activity at other well-established GPCRs, including the opioid, adenosine, serotonin, and dopamine receptor families. In addition, the cannabinoid receptors have also been shown to form dimers with other GPCRs triggering cross-talk signaling under specific conditions. In this mini review, we aim to provide insight into the non-CB₁, non-CB₂ cannabinoid-related GPCRs that have been reported thus far. We consider the physiological relevance of these molecular targets in modulating the ECS.