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Review
. 2017 Oct 1;2(1):265-273.
doi: 10.1089/can.2017.0036. eCollection 2017.

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

Paula Morales  1 , Patricia H Reggio  1
Affiliations
Review

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

Paula Morales et al. Cannabis Cannabinoid Res. .

Abstract

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.

Keywords: GPCRs; cannabinoid receptors; endocannabinoid system; orphan receptors.

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Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
Phylogenetic tree of cannabinoid receptors and the closely related Class A GPCRs (S1PR family and the orphan receptors GPR3, GPR6, and GPR12). Data were obtained from GPCRdb.org. CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; GPCR, G-protein-coupled receptor; S1P, sphingosine-1-phosphate.
<b>FIG. 2.</b>
FIG. 2.
Structures of the putative GPR3, GPR6, and GPR12 endogenous ligands S1P and SPC and the GPR3 and GPR6 inverse agonist CBD. SPC, sphingosylphosphorylcholine.
<b>FIG. 3.</b>
FIG. 3.
Alkylindole derivatives WIN55,212–2, ST-11, ST-23, ST-25, and ST-48.
See this image and copyright information in PMC

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