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Molecular Pharmacology

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Research ArticleArticle

Targeting a PAR4 carboxyl terminal motif to regulate platelet function

Rithwik Ramachandran, Koichiro Mihara, Pierre Thibeault, Christina M Vanderboor, Bjoern Petri, Mahmoud Saifeddine, Michel Bouvier and Morley D. Hollenberg
Molecular Pharmacology January 26, 2017, mol.116.106526; DOI: https://doi.org/10.1124/mol.116.106526
Rithwik Ramachandran
1 University of Western Ontario;
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Koichiro Mihara
2 University of Calgary;
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Pierre Thibeault
1 University of Western Ontario;
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Christina M Vanderboor
1 University of Western Ontario;
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Bjoern Petri
2 University of Calgary;
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Mahmoud Saifeddine
2 University of Calgary;
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Michel Bouvier
3 University of Montreal;
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Morley D. Hollenberg
4 The University of Calgary
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Abstract

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.

  • Thrombin
  • AKT / PKB
  • Platelets
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Research ArticleArticle

Targeting a PAR4 carboxyl terminal motif to regulate platelet function

Rithwik Ramachandran, Koichiro Mihara, Pierre Thibeault, Christina M Vanderboor, Bjoern Petri, Mahmoud Saifeddine, Michel Bouvier and Morley D. Hollenberg
Molecular Pharmacology January 26, 2017, mol.116.106526; DOI: https://doi.org/10.1124/mol.116.106526

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Research ArticleArticle

Targeting a PAR4 carboxyl terminal motif to regulate platelet function

Rithwik Ramachandran, Koichiro Mihara, Pierre Thibeault, Christina M Vanderboor, Bjoern Petri, Mahmoud Saifeddine, Michel Bouvier and Morley D. Hollenberg
Molecular Pharmacology January 26, 2017, mol.116.106526; DOI: https://doi.org/10.1124/mol.116.106526
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