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

FASEB J. 2009 Jan;23(1):183-93. doi: 10.1096/fj.08-108670. Epub 2008 Aug 29.

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 Ca(2+) release pathway, which is dependent on Galpha13 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 CB(1) antagonist AM251 evoked GPR55-mediated Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Signaling / physiology*
  • Cell Line
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Gene Expression Regulation
  • Humans
  • Lysophospholipids / pharmacology*
  • NFATC Transcription Factors / metabolism*
  • Protein Transport
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • GPR55 protein, human
  • Lysophospholipids
  • NFATC Transcription Factors
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled
  • lysophosphatidylinositol
  • GTP-Binding Protein alpha Subunits, G12-G13
  • rhoA GTP-Binding Protein