title: Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling.
abstract: Thrombin is known to signal to cells by cleaving/activating a G-protein-coupled family of proteinase-activated receptors (PARs). The signaling mechanism involves the proteolytic unmasking of an N-terminal receptor sequence that acts as a tethered receptor-activating ligand. To date, the recognized targets of thrombin cleavage and activation for signaling are PAR1 and PAR4, in which thrombin cleaves at a conserved target arginine to reveal a tethered ligand. PAR2, which like PAR1 is also cleaved at an N-terminal arginine to unmask its tethered ligand, is generally regarded as a target for trypsin but not for thrombin signaling. We now show that thrombin, at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment, can directly activate PAR2 vasorelaxation and signaling, stimulating calcium and mitogen-activated protein kinase responses along with triggeringβ-arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function.
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mihara
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Rithwik
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Saifeddine
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Hansen
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Bernard
authors.initials: B
authors.lastname: Renaux
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Danny
authors.initials: D
authors.lastname: Polley
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Stacy
authors.initials: S
authors.lastname: Gibson
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.).
authors.forename: Christina
authors.initials: C
authors.lastname: Vanderboor
authors.affiliation: Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.) mhollenb@ucalgary.ca.
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001011:Aorta; D019390:Arrestins / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis; D011817:Rabbits; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: C487404:2-furoyl-LIGRLO-amide; D019390:Arrestins; D008164:Luminescent Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D044464:Receptor, PAR-2; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; D013917:Thrombin