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

Research output: Contribution to journalArticle

188 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

The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. / Henstridge, Christopher M.; Balenga, Nariman A. B.; Ford, Lesley Ann; Ross, Ruth Alexandra; Waldhoer, Maria; Irving, Andrew J.

In: The FASEB Journal, Vol. 23, No. 1, 01.2009, p. 183-193.

Research output: Contribution to journalArticle

Henstridge, CM, Balenga, NAB, Ford, LA, Ross, RA, Waldhoer, M & Irving, AJ 2009, 'The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation', The FASEB Journal, vol. 23, no. 1, pp. 183-193. https://doi.org/10.1096/fj.08-108670
Henstridge, Christopher M. ; Balenga, Nariman A. B. ; Ford, Lesley Ann ; Ross, Ruth Alexandra ; Waldhoer, Maria ; Irving, Andrew J. / The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. In: The FASEB Journal. 2009 ; Vol. 23, No. 1. pp. 183-193.
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AU - Waldhoer, Maria

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AB - 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)

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KW - CALCIUM

KW - NEURONS

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KW - cannabinoid

KW - LPI

KW - AM251

KW - transcription

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JO - The FASEB Journal

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