The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation

Christopher M. Henstridge, Nariman A. B. Balenga, Lesley Ann Ford, Ruth Alexandra Ross, Maria Waldhoer, Andrew J Irving

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197 Citations (Scopus)

Abstract

The endogenous phospholipid L-alpha-lysophosphatidylinositol (LPI) was recently identified as a novel ligand for the orphan G protein-coupled receptor 55 (GPR55). In this study we define the downstream signaling pathways activated by LPI in a human embryonic kidney (HEK) 293 cell line engineered to stably express recombinant human GPR55. We find that treatment with LPI induces marked GPR55 internalization and stimulates a sustained, oscillatory Ca2+ release pathway, which is dependent on G alpha 13 and requires RhoA activation. We then establish that this signaling cascade leads to the efficient activation of NFAT (nuclear factor of activated T cells) family transcription factors and their nuclear translocation. Analysis of cannabinoid ligand activity at GPR55 revealed no clear effect of the endocannabinoids anandamide and 2-arachidonoylglycerol; however, the classical CB1 antagonist AM251 evoked GPR55-mediated Ca2+ signaling. Thus, LPI is a potent and efficacious ligand at GPR55, which is likely to be a key plasma membrane mediator of LPI- mediated signaling events and changes in gene expression.-Henstridge, C. M., Balenga, N. A. B., Ford, L. A., Ross, R. A., Waldhoer, M., Irving, A. J. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA- dependent Ca2+ signaling and NFAT activation. FASEB J. 23, 183-193 (2009)

Original languageEnglish
Pages (from-to)183-193
Number of pages11
JournalThe FASEB Journal
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 2009

Keywords

  • GPCR
  • cannabinoid
  • LPI
  • AM251
  • transcription
  • ROCK
  • CANNABINOID RECEPTOR
  • CONSTITUTIVE ENDOCYTOSIS
  • ENDOTHELIAL-CELLS
  • GENE-EXPRESSION
  • ANANDAMIDE
  • CALCIUM
  • NEURONS
  • GPCR
  • cannabinoid
  • LPI
  • AM251
  • transcription

Cite this

Henstridge, C. M., Balenga, N. A. B., Ford, L. A., Ross, R. A., Waldhoer, M., & Irving, A. J. (2009). The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. The FASEB Journal, 23(1), 183-193. https://doi.org/10.1096/fj.08-108670