TY - JOUR T1 - Targeting a PAR4 carboxyl terminal motif to regulate platelet function JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.106526 SP - mol.116.106526 AU - Rithwik Ramachandran AU - Koichiro Mihara AU - Pierre Thibeault AU - Christina M Vanderboor AU - Bjoern Petri AU - Mahmoud Saifeddine AU - Michel Bouvier AU - Morley D. Hollenberg Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/01/26/mol.116.106526.abstract N2 - Thrombin initiates human platelet aggregation by coordinately activating proteinase activated receptors (PARs)-1 and -4. However, targeting PAR1 with an orthostatic tethered ligand binding site antagonist results in bleeding, possibly due 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 are 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. ER -