Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.
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.
Kapur
Ankur
A
Department of Anatomy and Cell Biology and Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, USA.
Zhao
Pingwei
P
Sharir
Haleli
H
Bai
Yushi
Y
Caron
Marc G
MG
Barak
Larry S
LS
Abood
Mary E
ME
D000700:Analgesics / Q000494:pharmacology; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003511:Cyclohexanols / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D000071557:beta-Arrestins
D000700:Analgesics; D019390:Arrestins; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D003511:Cyclohexanols; C524885:GPR55 protein, human; D008024:Ligands; D008246:Lysophospholipids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C025449:lysophosphatidylinositol; C103505:AM 251; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077285:Rimonabant