Thrombin-mediated direct activation of proteinase-activated Receptor-2: Another target for thrombin signaling

Authors

Koichiro Mihara, University of Calgary
Rithwik Ramachandran, University of Calgary
Mahmoud Saifeddine, University of Calgary
Kristina K. Hansen, University of Calgary
Bernard Renaux, University of Calgary
Danny Polley, University of Calgary
Stacy Gibson, University of Calgary
Christina Vanderboor, Western University
Morley D. Hollenberg, University of Calgary

Document Type

Article

Publication Date

5-1-2016

Journal

Molecular Pharmacology

Volume

89

Issue

5

First Page

606

Last Page

614

URL with Digital Object Identifier

10.1124/mol.115.102723

Abstract

Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics. 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 vaso-relaxation 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.