Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.

Article Details


Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME

Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.

J Biol Chem. 2009 Oct 23;284(43):29817-27. doi: 10.1074/jbc.M109.050187. Epub 2009 Sep 1.

PubMed ID
19723626 [ View in PubMed

The cannabinoid receptor 1 (CB(1)) and CB(2) cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a beta-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing beta-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CbetaII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of beta-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CbetaII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
RimonabantG-protein coupled receptor 55ProteinHumans
Not AvailableDetails
NameUniProt ID
G-protein coupled receptor 55Q9Y2T6Details