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A Selective Antagonist Reveals a Potential Role of G Protein-Coupled

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A Selective Antagonist Reveals a Potential Role of G Protein-Coupled JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 JPETThis Fast article Forward. has not been Published copyedited and on formatted. May 2, The 2013 final as version DOI:10.1124/jpet.113.204180 may differ from this version. JPET #204180 Title Page A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function Julia Kargl*, Andrew J Brown, Liisa Andersen, Georg Dorn, Rudolf Schicho, Maria Waldhoer and Akos Heinemann Downloaded from Primary laboratory of origin: Institute for Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria jpet.aspetjournals.org Affiliation: Institute for Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria at ASPET Journals on September 26, 2021 (J.K., L.A., G.D., R.S., M.W., A.H.); Screening and Compound Profiling, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK (A.J.B); current address: Hagedorn Research Institute, Novo Nordisk A/S, 2820-Gentofte, Denmark (M.W.) 1 Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 Running Title Page Characterization of a GPR55 antagonist *Corresponding author: Julia Kargl Institute for Experimental and Clinical Pharmacology Medical University of Graz 8010 Graz, Austria Downloaded from Telefon: +43 316 380 - 7851 Fax: +43 316 380 - 9645 Email : [email protected] jpet.aspetjournals.org Number of text pages: 35 Number of tables: 1 at ASPET Journals on September 26, 2021 Number of figures: 8 Number of references: 47 Number of words in Abstract: 186 Number of words in Introduction: 750 Number of words in Discussion: 1253 Abbreviations: AM251 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide]; AM281 [1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3- carboxamide]; CB1, cannabinoid 1 receptor; CB2, cannabinoid 2 receptor; CID16020046, 4-[4-(3- hydroxyphenyl)-3-(4-methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo [3,4-c] pyrazol-5-yl] benzoic acid; CNS, central nervous system; DMEM, Dulbecco´s modified Eagle´s Medium; DMSO, Dimethylsulfoxid; ERK, Extracellular-signal Regulated Kinase; FBS, Fetal Bovine Serum; GPCR, G protein coupled receptor; GPR55, G protein coupled eceptor 55; HA, haemaglutinin; HEK293, human 2 JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 embryonic kidney cells; HRP, Horseradish peroxidase; IgG, Immunglobulin G; LPI, L-α- lysophosphatidylinositol; MAPK, mitogen-activated protein kinases; PBS, Phosphate buffered saline; PNGase, N-Glycosidase; SR141716A [5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N- (piperidin-1-yl)-1H-pyrazole-3-carboxamide]; TBS, Tris-Buffered Saline; WIN55,212–2 [(R)-(_)-[2,3- dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1- naphthalenylmethanone] Downloaded from Recommended section assignment: Cellular and Molecular jpet.aspetjournals.org at ASPET Journals on September 26, 2021 3 JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 Abstract The G protein coupled receptor 55 (GPR55) is a lysophosphatidylinositol (LPI) receptor that is also responsive to certain cannabinoids. Although GPR55 has been implicated in several (patho)physiological functions, its role is still enigmatic mainly owing to the lack of selective GPR55 antagonists. Here we show that the compound CID16020046 ((4-[4-(3-hydroxyphenyl)-3-(4- methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo [3,4-c] pyrazol-5-yl] benzoic acid) is a selective GPR55 antagonist. In yeast cells expressing human GPR55, CID16020046 antagonized agonist-induced receptor activation. In HEK293 cells stably expressing human GPR55 (HEK-GPR55), the compound Downloaded from behaved as an antagonist on LPI-mediated Ca2+ release and extracellular signal-regulated kinases (ERK1/2) activation, but not in HEK293 cells expressing cannabinoid receptor 1 or 2 (CB1 or CB2). CID16020046 concentration-dependently inhibited LPI-induced activation of nuclear factor of jpet.aspetjournals.org activated T-cells (NFAT), nuclear factor kappa of activated B cells (NF-κB) and serum response element (SRE), translocation of NFAT and NF-κB, and GPR55 internalization. It reduced LPI-induced wound healing in primary human lung microvascular endothelial cells (HMVEC-L) and reversed LPI- at ASPET Journals on September 26, 2021 inhibited platelet aggregation, suggesting a novel role for GPR55 in platelet and endothelial cell function. CID16020046 is therefore a valuable tool to study GPR55-mediated mechanisms in primary cells and tissues. 4 JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 Introduction Cannabinoids bind to and induce signaling via the cannabinoid 1 (CB1) and the cannabinoid 2 (CB2) receptors. Nevertheless, studies on cannabinoid receptor knock-out mice suggested additional cannabinoid-sensitive targets (Mackie and Stella, 2006;Brown, 2007). One receptor for small lipid mediators and synthetic cannabinoids is the G protein-coupled receptor 55 (GPR55). GPR55 is highly abundant in the CNS as well as in intestine, bone marrow, spleen, platelets, immune and endothelial cells (Balenga et al., 2011a; Henstridge et al., 2011; Waldeck-Weiemair et al., 2008; Sawzdargo et al., 1999; Ryberg et al., 2007; Pietr et al., 2009; Rowley et al., 2011). Moreover, GPR55 was detected in a Downloaded from variety of cancer tissues and cancer cell lines (Andradas et al., 2011; Pineiro et al., 2011; Ford et al., 2010; Huang et al., 2011; Perez-Gomez et al., 2012). Several endogenous GPR55 signaling pathways have been described to date despite controversial findings concerning its agonists and antagonists jpet.aspetjournals.org (Balenga et al., 2011b). One consensus between several groups is that GPR55 couples to Gα13 and/or Gαq proteins in HEK293 cells that transiently or stably express GPR55 (Henstridge et al., 2009; Ryberg et al., 2007; Sharir and Abood, 2010; Lauckner et al., 2008; Henstridge et al., 2010; Schroder et al., at ASPET Journals on September 26, 2021 2010). In addition, GPR55 has been reported to activate small GTPases (Henstridge et al., 2009; Balenga et al., 2011a; Ryberg et al., 2007) and to induce calcium release from intracellular stores (Henstridge et al., 2009; Henstridge et al., 2010; Oka et al., 2007; Brown, et al., 2011). Further downstream, GPR55 activation has been shown to lead to the activation of several transcription factors, such as nuclear factor of activated T-cells (NFAT), nuclear factor kappa of activated B cells (NF-κB), serum response element (SRE), cyclic AMP response element-binding protein (CREB) and activating transcription factor 2 (ATF2) (Kargl et al., 2012a; Henstridge et al., 2009; Henstridge et al., 2010; Oka et al., 2010). In addition, MAP-kinases, such as p38 and extracellular signal-regulated kinases (ERK1/2), are activated upon GPR55 stimulation (Oka et al., 2010; Henstridge et al., 2010). The lipid lysophosphatidylinositol (LPI) has been described as the first endogenous ligand for GPR55 by Oka et al. (Oka et al., 2007). In addition, several synthetic CB1 receptor inverse agonists/antagonists, such as AM251, AM281 and rimonabant (SR141716A) have been shown to activate GPR55 (Henstridge et al., 2009; Ryberg et al., 2007; Henstridge et al., 2010; Oka et al., 2007; Brown et al., 2011; Kapur et al., 2009; Yin et al., 2009). Although several cannabinoid ligands can 5 JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 activate GPR55, the receptor lacks the classical “cannabinoid binding pocket” (Kotsikorou et al., 2011). Screening approaches have identified selective GPR55 agonists, such as GSK319197A or GSK494581A (Kargl et al., 2012a; Brown et al., 2011), which generally appear to be inactive at CB1 and CB2 receptors, and hence are promising tools to elucidate the pharmacological, physiological and pathophysiological functions of GPR55. The first such chemical series of synthetic GPR55 agonists to be described were the benzoylpiperazines. Importantly, benzoylpiperazines were independently identified at GlaxoSmithKline (Brown et al., 2011; Kargl et al., 2012a) and by the National Institutes Downloaded from of Health Molecular Libraries Probe Identification program (Heynen-Genel et al., 2010b; Kotsikorou et al., 2011). The latter screen utilised β-arrestin fluorescent protein biosensors and identified further agonists as well as antagonists (Heynen-Genel et al., 2010b; Heynen-Genel et al., 2010a). However, jpet.aspetjournals.org there is so far only limited characterization of these antagonists in peer-reviewed literature. The lipid ligand LPI, the CB1 receptor inverse agonists/antagonists SR141716A, AM251 and AM281 and selective GPR55 agonists were described to activate transcription factors in human embryonic at ASPET Journals on September
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