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

Koichiro Mihara1, Rithwik Ramachandran1, Mahmoud Saifeddine1

  • 1Inflammation 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.).

Molecular Pharmacology
|March 10, 2016
PubMed

Insights

Thrombin directly activates proteinase-activated receptor 2 (PAR2) signaling, previously thought to be activated only by trypsin. This finding expands the known roles of thrombin in cellular signaling and tissue function.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Physiology

Background:

  • Thrombin activates G-protein-coupled receptors (PARs) via proteolytic cleavage, unmasking a tethered ligand.
  • PAR1 and PAR4 are established thrombin signaling targets, activated at a conserved arginine residue.
  • PAR2 is typically activated by trypsin, not thrombin, despite also being cleaved at an N-terminal arginine.

Purpose of the Study:

  • To investigate whether thrombin can directly activate PAR2.
  • To characterize the signaling pathways downstream of thrombin-mediated PAR2 activation.

Main Methods:

  • In vitro assays measuring vasorelaxation.
  • Calcium imaging to assess intracellular calcium mobilization.
  • Western blotting for mitogen-activated protein kinase (MAPK) activation.
  • β-arrestin recruitment assays.

Main Results:

  • Thrombin directly activates PAR2 at concentrations relevant to injury and tumor microenvironments.
  • PAR2 activation by thrombin stimulates calcium and MAPK signaling.
  • Thrombin-induced PAR2 activation triggers β-arrestin recruitment.

Conclusions:

  • PAR2 should be recognized as a direct signaling target of thrombin, alongside PAR1 and PAR4.
  • Thrombin's ability to activate PAR2 expands its known mechanisms for affecting tissue function.

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