Endocannabinoids are increasingly being recognized as key lipid-derived regulators of immune function 1. Although the peripheral cannabinoid type 2 receptor (CB2) is thought to orchestrate many of these actions, additional non-CB1/CB2-mediated effects of cannabinoids have been identified in immune cells 1, 2, where several orphan G protein-coupled receptors (GPCRs), including the effusive GPR55, are implicated 3. Despite numerous studies addressing the cannabinoid sensitivity of GPR55, the area remains a pharmacological minefield, with much inconsistent and conflicting data. Emerging provocatively from behind the marijuana smokescreen is a rather surprising, endogenous, lipid ligand at GPR55: namely lysophosphaditylinositol (LPI; 4). In this issue of Cell Research, Balenga and colleagues 5 demonstrates that LPI and the cannabinoid antagonist AM251, have prominent effects on neutrophils that are mediated by GPR55, providing the first compelling evidence for functional GPR55 in blood. In addition, they show that GPR55 forms an intimate but mercurial partnership with the CB2receptor and that crosstalk between these lipid-sensing GPCRs is likely to be important in fine-tuning the immune response to abrogate excessive tissue injury.
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