Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids

Sharon Anavi-Goffer* (Corresponding Author), Gemma Baillie, Andrew Irving, Juerg Gertsch, Iain R. Greig, Roger G. Pertwee, Ruth A. Ross

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)


GPR55 is activated by l-a-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®, 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® SureFire® 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 ¿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 pages15
JournalThe Journal of Biological Chemistry
Issue number1
Early online date25 Oct 2011
Publication statusPublished - 2 Jan 2012


  • allosteric regulation
  • cannabinoid receptors
  • cannabinoids
  • G protein-coupled receptors (GPCR)
  • pharmacology
  • acomplia
  • AlphaScreen
  • bitopic ligand
  • GPR55
  • PLX-4720 BRAF inhibitor


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