Modulation of L-alpha-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids

Sharon Anavi-Goffer, Gemma Baillie, Andrew J. Irving, Juerg Gertsch, Iain R. Greig, Roger G. Pertwee, Ruth A. Ross

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    83 Citations (Scopus)

    Abstract

    GPR55 is activated by L-alpha-lysophosphatidylinositol (LPI) but also by certain cannabinoids. In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant (R), CB2 receptor agonists, and Cannabis sativa constituents. To test ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys LPI-induced activation of GPR55, a high throughput system, was established using the AlphaScreen (R) SureFire (R) assay. Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands. The phytocannabinoids Delta(9)-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.

    Original languageEnglish
    Pages (from-to)91-104
    Number of pages14
    JournalJournal of Biological Chemistry
    Volume287
    Issue number1
    DOIs
    Publication statusPublished - 2 Jan 2012

    Keywords

    • L-ALPHA-LYSOPHOSPHATIDYLINOSITOL
    • CANCER-CELL PROLIFERATION
    • CB1 RECEPTOR ANTAGONIST
    • B-RAF INHIBITORS
    • ALLOSTERIC MODULATION
    • PLANT CANNABINOIDS
    • ENDOTHELIAL-CELLS
    • NEUROPATHIC PAIN
    • GPR55
    • IDENTIFICATION

    Cite this

    Anavi-Goffer, S., Baillie, G., Irving, A. J., Gertsch, J., Greig, I. R., Pertwee, R. G., & Ross, R. A. (2012). Modulation of L-alpha-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids. Journal of Biological Chemistry, 287(1), 91-104. https://doi.org/10.1074/jbc.M111.296020