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, 152 (5), 567-75

Novel Cannabinoid Receptors


Novel Cannabinoid Receptors

A J Brown. Br J Pharmacol.


Cannabinoids have numerous physiological effects. In the years since the molecular identification of the G protein-coupled receptors CB1 and CB2, the ion channel TRPV1, and their corresponding endogenous ligand systems, many cannabinoid-evoked actions have been shown conclusively to be mediated by one of these specific receptor targets. However, there remain several examples where these classical cannabinoid receptors do not explain observed pharmacology. Studies using mice genetically deleted for the known receptors have confirmed the existence of additional targets, which have come to be known collectively as non-CB1/CB2 receptors. Despite intense research efforts, the molecular identity of these non-CB1/CB2 receptors remains for the most part unclear. Two orphan G protein-coupled receptors have recently been implicated as novel cannabinoid receptors; these are GPR119, which has been proposed as a receptor for oleoylethanolamide, and GPR55 which has been proposed as a receptor activated by multiple different cannabinoid ligands. In this review I will present an introduction to non-CB1/CB2 pharmacology, summarize information on GPR55 and GPR119 currently available, and consider their phylogenetic origin and what aspects of non-CB1/CB2 pharmacology, if any, they help explain.


Figure 1
Figure 1
Phylogenetic analysis of all non-sensory human family A G protein-coupled receptors (GPCRs; adapted from Foord, 2007). The neighbour-joining method was used, after forced alignment according to common amino-acid motifs. Each line represents a GPCR; known and putative cannabinoid receptors and other receptors described in this review are identified. Clusters have been assigned to groups (Foord, 2007): group 1, the monoamine-like receptors; group 2, a diverse group containing opsins and glycoprotein/leucine-rich repeat (LRG) type as well as cannabinoid, prostaglandin and lipid receptors; group 3, brain/gut peptide receptors; group 4, chemokine receptors; and group 5, metabolic receptors including purinergic, thrombin and free-fatty acid receptors. Cross-species comparisons show that groups 4 and 5 are not found in nematodes and insects. Abbreviations: CNR1 and CNR2 are the genes encoding cannabinoid type 1 receptor (CB1) and cannabinoid type 2 receptor (CB2), respectively. EDG indicates the sphingolipid receptor cluster, which comprises LPA1/EDG2, LPA2/EDG4 and LPA3/EDG7 and the sphingosine-1-phosphate (S1P) receptors (S1P1 to S1P5). LPA, lysophosphatidic acid.

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