Publications

← Retour à la liste complète des publications

Targeting a Proteinase-Activated Receptor 4 (PAR4) Carboxyl Terminal Motif to Regulate Platelet Function.

Ramachandran R, Mihara K, Thibeault P, Vanderboor CM, Petri B, Saifeddine M, Bouvier M, Hollenberg MD

Snyder Institute for Chronic Diseases and Department of Physiology and Pharmacology (R.R., K.M., M.S., M.D.H.), Mouse Phenomics Resource Laboratory, Snyder Institute for Chronic Diseases and Department of Microbiology, Immunology, and Infectious Diseases (B.P.), and Department of Medicine (M.D.H.), Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada (R.R., P.T., C.M.V.); and IRIC-Université de Montréal, Montréal, Québec, Canada (M.B.) rramach@uwo.ca.

Thrombin initiates human platelet aggregation by coordinately activating proteinase-activated receptors (PARs) 1 and 4. However, targeting PAR1 with an orthosteric-tethered ligand binding-site 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 β-arrestin interactions. By disrupting this PAR4 calcium/β-arrestin signaling process with a novel cell-penetrating peptide, we were able to inhibit both thrombin-triggered 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.

Mol. Pharmacol. 2017;91(4):287-295.

Pubmed ID: 28126849

Suivez l'IRIC

Logo UdeM