PT  - JOURNAL ARTICLE
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
TI  - Targeting a PAR4 carboxyl terminal motif to regulate platelet function
AID  - 10.1124/mol.116.106526
DP  - 2017 Jan 01
TA  - Molecular Pharmacology
PG  - mol.116.106526
4099  - http://molpharm.aspetjournals.org/content/early/2017/01/26/mol.116.106526.short
4100  - http://molpharm.aspetjournals.org/content/early/2017/01/26/mol.116.106526.full
AB  - 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.