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

Christopher M. Henstridge^*,1, Nariman A. B. Balenga^,1, Lesley A. Ford, Ruth A. Ross, Maria Waldhoer^,2 and Andrew J. Irving^*,2

^* Centre for Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK;

Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria; and

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

² Correspondence: A.J.I., Centre for Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. E-mail: a.j.irving{at}dundee.ac.uk; M.W., Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria. E-mail: maria.waldhoer{at}meduni-graz.at

The endogenous phospholipid L--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 G13 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--lysophosphatidylinositol promotes RhoA-dependent Ca²⁺ signaling and NFAT activation.

Key Words: GPCR • cannabinoid • LPI • AM251 • transcription • ROCK