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

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

Research output: Contribution to journalArticle

186 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
JournalFASEB Journal
Volume23
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • Calcium Signaling
  • Cell Line
  • GTP-Binding Protein alpha Subunits, G12-G13
  • Gene Expression Regulation
  • Humans
  • Lysophospholipids
  • NFATC Transcription Factors
  • Protein Transport
  • Receptors, G-Protein-Coupled
  • rhoA GTP-Binding Protein

Cite this

Henstridge, Christopher M. ; Balenga, Nariman A. B. ; Ford, Lesley A. ; Ross, Ruth A. ; Waldhoer, Maria ; Irving, Andrew J. / The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. In: FASEB Journal. 2009 ; Vol. 23, No. 1. pp. 183-193.
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The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. / Henstridge, Christopher M.; Balenga, Nariman A. B.; Ford, Lesley A.; Ross, Ruth A.; Waldhoer, Maria; Irving, Andrew J.

In: FASEB Journal, Vol. 23, No. 1, 2009, p. 183-193.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation

AU - Henstridge, Christopher M.

AU - Balenga, Nariman A. B.

AU - Ford, Lesley A.

AU - Ross, Ruth A.

AU - Waldhoer, Maria

AU - Irving, Andrew J.

PY - 2009

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N2 - 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)

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)

KW - Calcium Signaling

KW - Cell Line

KW - GTP-Binding Protein alpha Subunits, G12-G13

KW - Gene Expression Regulation

KW - Humans

KW - Lysophospholipids

KW - NFATC Transcription Factors

KW - Protein Transport

KW - Receptors, G-Protein-Coupled

KW - rhoA GTP-Binding Protein

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DO - 10.1096/fj.08-108670

M3 - Article

VL - 23

SP - 183

EP - 193

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 1

ER -