Journal
MOLECULAR PHARMACOLOGY
Volume 91, Issue 4, Pages 287-U230Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.116.106526
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- Snyder Mouse Phenomics Resources Laboratory - Snyder Institute for Chronic Diseases at the University of Calgary
- Live Cell Imaging Facility - Snyder Institute for Chronic Diseases at the University of Calgary
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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 beta-arrestin interactions. By disrupting this PAR4 calcium/beta-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.
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