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Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu / Tam, Joseph


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

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2191-0286
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Volume 27, Issue 3

Issues

Modulation of l-α-lysophosphatidylinositol/GPR55 MAP kinase signalling by CB2 receptor agonists: identifying novel GPR55 inhibitors

Sharon Anavi-Goffer
  • Corresponding author
  • Department of Behavioral Sciences, Ariel University, Ariel 40700, Israel
  • School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Andrew J. Irving
  • School of Biomolecular and Biomedical Science, The Conway Institute, University College Dublin, Dublin, Ireland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ruth A. Ross
  • Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
  • School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-04-18 | DOI: https://doi.org/10.1515/jbcpp-2015-0142

Abstract

Background: GPR55 is a lipid-sensing G protein-coupled receptor that is activated by the endogenous lipid l-α-lysophosphatidylinositol (LPI) and can be modulated by certain cannabinoid ligands.

Methods: In this study we investigated the GPR55 activity of four synthetic CB2 receptor agonists using the AlphaScreen® SureFire® assay.

Results: Here we show that the CB2 receptor-selective agonists HU-308, HU-433 and HU-910 do not promote GPR55-mediated ERK1/2 phosphorylation up to a concentration of 3 μM. However, LPI-induced ERK1/2 phosphorylation is inhibited by the (–)-enantiomer of HU-308, designated HU-433, whereas HU-308 has no effect on LPI activity. The carboxylic analogue of HU-910, designated HU-914, potently inhibits LPI-induced ERK1/2 phosphorylation; however, HU-914 was less effective, with potential biphasic effects.

Conclusions: This structure-activity-relationship study has identified novel ligands which act both as CB2 receptor agonists and GPR55 modulators and related compounds that lack GPR55 activity.

Keywords: AlphaScreen; cannabinoids; CB2 receptor-selective agonists; endocannabinoids; ERK1/2; GPR55

References

  • 1.

    Moreno-Navarrete JM, Catalan V, Whyte L, Diaz-Arteaga A, Vazquez-Martinez R, Rotellar F, et al. The L-alpha-lysophosphati dylinositol/GPR55 system and its potential role in human obesity. Diabetes 2012;61:281–91.Google Scholar

  • 2.

    Ishiguro H, Onaivi ES, Horiuchi Y, Imai K, Komaki G, Ishikawa T, et al. Functional polymorphism in the GPR55 gene is associated with anorexia nervosa. Synapse 2011;65:103–8.Web of ScienceGoogle Scholar

  • 3.

    Perez-Gomez E, Andradas C, Flores JM, Quintanilla M, Paramio JM, Guzman M, et al. The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas. Oncogene 2013;32:2534–42.Web of ScienceGoogle Scholar

  • 4.

    Hu G, Ren G, Shi Y. The putative cannabinoid receptor GPR55 promotes cancer cell proliferation. Oncogene 2011;30:139–41.Web of ScienceGoogle Scholar

  • 5.

    Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, et al. A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol 2010;160:762–71.Google Scholar

  • 6.

    Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, et al. Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 2009;284:29817–27.Google Scholar

  • 7.

    Kotsikorou E, Sharir H, Shore DM, Hurst DP, Lynch DL, Madrigal KE, et al. Identification of the GPR55 antagonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 2013;52:9456–69.Web of ScienceGoogle Scholar

  • 8.

    Sharir H, Abood ME. Pharmacological characterization of GPR55, a putative cannabinoid receptor. Pharmacol Ther 2010;126:301–13.Google Scholar

  • 9.

    Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, et al. Modulation of L-alpha-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem 2012;287:91–104.Google Scholar

  • 10.

    Heynen-Genel S, Dahl R, Shi S, Milan L, Hariharan S, Bravo Y, et al. Screening for selective ligands for GPR55 agonists in Probe Reports from the NIH Molecular Libraries Program (Internet), National Center for Biotechnology Information, Bethesda, MD, NBK66152 [bookaccession], 2010.Google Scholar

  • 11.

    Henstridge CM, Balenga NA, Schroder R, Kargl JK, Platzer W, Martini L, et al. GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol 2010;160:604–14.Google Scholar

  • 12.

    Sharir H, Console-Bram L, Mundy C, Popoff SN, Kapur A, Abood ME. The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55. J Neuroimmune Pharmacol 2012;7:856–65.Google Scholar

  • 13.

    Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 2011;30:245–52.Google Scholar

  • 14.

    Pineiro R, Maffucci T, Falasca M. The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene 2011;30:142–52.Web of ScienceGoogle Scholar

  • 15.

    Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC, Jr., LaPolla JP, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev 2004;13:1185–91.Google Scholar

  • 16.

    Heynen-Genel S, Dahl R, Shi S, Milan L, Hariharan S, Sergienko E, et al. Screening for selective ligands for GPR55 antagonists in Probe Reports from the NIH Molecular Libraries Program (Internet), National Center for Biotechnology Information, Bethesda, MD, NBK66153 [bookaccession], 2010.Google Scholar

  • 17.

    Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 2008;139:225–36.Web of ScienceGoogle Scholar

  • 18.

    Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci USA 2009;106:16511–6.Google Scholar

  • 19.

    Wu CS, Chen H, Sun H, Zhu J, Jew CP, Wager-Miller J, et al. GPR55, a G-protein coupled receptor for lysophosphatidylinositol, plays a role in motor coordination. PLoS One 2013;8:e60314.Google Scholar

  • 20.

    Balenga NA, Aflaki E, Kargl J, Platzer W, Schroder R, Blattermann S, et al. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Res 2011;21:1452–69.Web of ScienceGoogle Scholar

  • 21.

    Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 2009;23:183–93.Google Scholar

  • 22.

    Horvath B, Magid L, Mukhopadhyay P, Batkai S, Rajesh M, Park O, et al. A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. Br J Pharmacol 2012;165:2462–78.Web of ScienceGoogle Scholar

  • 23.

    Smoum R, Baraghithy S, Chourasia M, Breuer A, Mussai N, Attar-Namdar M, et al. CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse relationship between binding affinity and biological potency. Proc Natl Acad Sci USA 2015;112:8774–9.Google Scholar

  • 24.

    Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 2007;362:928–34.Google Scholar

  • 25.

    Schwartz TW, Holst B. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol Sci 2007;28:366–73.Web of ScienceGoogle Scholar

  • 26.

    Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 2010;160:467–79.Google Scholar

  • 27.

    Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 2006;103:696–701.Google Scholar

  • 28.

    Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 1999;96:14228–33.Google Scholar

  • 29.

    Genn RF, Tucci S, Marco EM, Viveros MP, File SE. Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test. Pharmacol Biochem Behav 2004;77:567–73.Google Scholar

  • 30.

    Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK, Mahadevan A, et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol 2005;145:293–300.Google Scholar

  • 31.

    Rey AA, Purrio M, Viveros MP, Lutz B. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 2012;37:2624–34.Web of ScienceGoogle Scholar

About the article

Received: 2015-11-20

Accepted: 2016-03-03

Published Online: 2016-04-18

Published in Print: 2016-05-01


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, Volume 27, Issue 3, Pages 303–310, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2015-0142.

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