Targeting a proteinase-activated receptor 4 (PAR4) carboxyl terminal motif to regulate platelet function

Authors

Rithwik Ramachandran, University of Calgary
Koichiro Mihara, University of Calgary
Pierre Thibeault, University of Calgary
Christina M. Vanderboor, University of Calgary
Björn Petri, University of Calgary
Mahmoud Saifeddine, University of Calgary
Michel Bouvier, University of Montreal
Morley D. Hollenberg, University of Calgary

Document Type

Article

Publication Date

4-1-2017

Journal

Molecular Pharmacology

Volume

91

Issue

4

First Page

287

Last Page

295

URL with Digital Object Identifier

10.1124/mol.116.106526

Abstract

© 2017 by The American Society for Pharmacology and Experimental Therapeutics. Thrombin initiates human platelet aggregation by coordinately activating proteinase-activated receptors (PARs) 1 and 4. However, targeting PAR1 with an orthosteric-tethered ligand bindingsite antagonist results in bleeding, possibly owing to the important role of PAR1 activation on cells other than platelets. Because of its more restricted tissue expression profile, we have therefore turned to PAR4 as an antiplatelet target. We have identified an intracellular PAR4 C-terminal motif that regulates calcium signaling and b-arrestin interactions. By disrupting this PAR4 calcium/b-arrestin signaling process with a novel cellpenetrating peptide, we were able to inhibit both thrombintriggered platelet aggregation in vitro and clot consolidation in vivo. We suggest that targeting PAR4 represents an attractive alternative to blocking PAR1 for antiplatelet therapy in humans.