title: A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function.
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)physiologic functions, its role remains enigmatic owing mainly 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 human embryonic kidney (HEK293) cells stably expressing human GPR55, the compound behaved as an antagonist on LPI-mediated Ca²⁺ release and extracellular signal-regulated kinases 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 activated T-cells (NFAT), nuclear factor κ of activated B cells (NF-κB) and serum response element, translocation of NFAT and NF-κB, and GPR55 internalization. It reduced LPI-induced wound healing in primary human lung microvascular endothelial cells and reversed LPI-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.
authors: Institute for Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria. julia.kargl@medunigraz.at
authors: Julia
authors: J
authors: Kargl
authors: Andrew J
authors: AJ
authors: Brown
authors: Liisa
authors: L
authors: Andersen
authors: Georg
authors: G
authors: Dorn
authors: Rudolf
authors: R
authors: Schicho
authors: Maria
authors: M
authors: Waldhoer
authors: Akos
authors: A
authors: Heinemann
mesh_terms: D053961:Azabicyclo Compounds / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000941:ethics; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013450:Sulfones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
chemical_list: C583127:(4-(3,4-dichlorophenyl)piperazin-1-yl)-(4'-fluoro-4-methanesulfonylbiphenyl-2-yl)methanone; C583126:4-(4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo(3,4-c)pyrazol-5-yl)benzoic acid; D053961:Azabicyclo Compounds; D001565:Benzoates; C571130:CNR1 protein, human; D063387:Cannabinoid Receptor Antagonists; C524885:GPR55 protein, human; D008024:Ligands; D008246:Lysophospholipids; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D010879:Piperazines; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D013450:Sulfones; C025449:lysophosphatidylinositol