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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling

Koichiro Mihara, Rithwik Ramachandran, Mahmoud Saifeddine, Kristina K. Hansen, Bernard Renaux, Danny Polley, Stacy Gibson, Christina Vanderboor and Morley D. Hollenberg
Molecular Pharmacology May 2016, 89 (5) 606-614; DOI: https://doi.org/10.1124/mol.115.102723
Koichiro Mihara
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.)
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Rithwik Ramachandran
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.)
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Mahmoud Saifeddine
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.)
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Kristina K. Hansen
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.)
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Bernard Renaux
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.)
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Danny Polley
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.)
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Stacy Gibson
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.)
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Christina Vanderboor
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.)
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Morley D. Hollenberg
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.)
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This article has a correction. Please see:

  • Correction to: “Inhibition of GLI1 Expression by Targeting the CRD-BP–GLI1 mRNA Interaction Using a Specific Oligonucleotide” - June 01, 2016

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 triggering β–arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function.

Footnotes

    • Received December 12, 2015.
    • Accepted March 3, 2016.
  • These studies were supported in large part by an operating grant from the Canadian Institutes of Health Research (MDH), with ancillary funding from Prostate Cancer Canada, The Calgary Prostate Cancer Centre and the Calgary Motorcycle Ride for Dad. Over part of the time frame of these studies, K.K.H. and R.R. were supported in part by postdoctoral fellowships from the Alberta Heritage Foundation for Medical Research (now: Alberta Innovates Heath Solutions).

  • dx.doi.org/10.1124/mol.115.102723.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (5)
Molecular Pharmacology
Vol. 89, Issue 5
1 May 2016
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Rapid CommunicationAccelerated Communication

Direct Thrombin Activation of PAR2

Koichiro Mihara, Rithwik Ramachandran, Mahmoud Saifeddine, Kristina K. Hansen, Bernard Renaux, Danny Polley, Stacy Gibson, Christina Vanderboor and Morley D. Hollenberg
Molecular Pharmacology May 1, 2016, 89 (5) 606-614; DOI: https://doi.org/10.1124/mol.115.102723

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Rapid CommunicationAccelerated Communication

Direct Thrombin Activation of PAR2

Koichiro Mihara, Rithwik Ramachandran, Mahmoud Saifeddine, Kristina K. Hansen, Bernard Renaux, Danny Polley, Stacy Gibson, Christina Vanderboor and Morley D. Hollenberg
Molecular Pharmacology May 1, 2016, 89 (5) 606-614; DOI: https://doi.org/10.1124/mol.115.102723
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