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Molecular Pharmacology

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Research ArticleArticle

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Michael Holinstat, Bryan Voss, Matthew L. Bilodeau and Heidi E. Hamm
Molecular Pharmacology March 2007, 71 (3) 686-694; DOI: https://doi.org/10.1124/mol.106.029371
Michael Holinstat
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Bryan Voss
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Matthew L. Bilodeau
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Heidi E. Hamm
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Abstract

Pathological conditions such as coronary artery disease are clinically controlled via therapeutic regulation of platelet activity. Thrombin, through protease-activated receptor (PAR) 1 and PAR4, plays a central role in regulation of human platelet function in that it is known to be the most potent activator of human platelets. Currently, direct thrombin inhibitors used to block platelet activation result in unwanted side effects of excessive bleeding. An alternative therapeutic strategy would be to inhibit PAR-mediated intracellular platelet signaling pathways. To elucidate the best target, we are studying differences between the two platelet thrombin receptors, PAR1 and PAR4, in mediating thrombin's action. In this study, we show that platelet activation by PAR1-activating peptide (PAR1-AP) requires a phospholipase D (PLD)-mediated phosphatidic acid (PA) signaling pathway. We show that this PAR1-specific PA-mediated effect is not regulated through differential granule secretion after PAR-induced platelet activation. Perturbation of this signaling pathway via inhibition of lipid phosphate phosphatase-1 (LPP-1) by propranolol or inhibition of the phosphatidylcholine-derived phosphatidic acid (PA) formation by PLD with a primary alcohol significantly attenuated platelet activation by PAR1-AP. Platelet activation by thrombin or PAR4-AP was insensitive to these inhibitors. Furthermore, these inhibitors significantly attenuated activation of Rap1 after stimulation by PAR1-AP but not thrombin or PAR4-AP. Because PA metabolites such as diacylglycerol play an important role in intracellular signaling, identifying crucial differences in PA regulation of PAR-induced platelet activation may lead to a greater understanding of the role of PAR1 versus PAR4 in progression of thrombosis.

Footnotes

  • This work was supported by National Institutes of Health grants HL060678, EY010291, 1P50-HL081009-01 (to H.E.H.) and National Research Service Awards (to M.H.) HL-082068-01. This work has been presented previously in abstract form: Holinstat M, Voss B, Bilodeau ML, and Hamm HE (2006) PAR1, but not PAR4, regulates human platelet activation through PLD. 2006 Experimental Biology; April 1–5, 2006; San Francisco, CA. Abstract 437.9.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.029371.

  • ABBREVIATIONS: PAR, protease-activated receptor; PKC, protein kinase C; GEF, guanine nucleotide exchange factor; DAG, diacylglycerol; PLC, phospholipase C; PLD, phospholipase D; PA, phosphatidic acid; PC, phosphatidylcholine; LPP-1, lipid phosphate phosphatase-1; AP, activating peptide; OAG, 1-oleoyl-2-acetyl-sn-glycerol; PMA, phorbol 12-myristate 13-acetate; FITC, fluorescein isothiocyanate; TCA, trichloroacetic acid; OPT, o-phthalaldehyde; RBD, Rap1-binding domain; β-AR, β adrenergic receptor; FACS, fluorescence-activated cell sorting.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received August 7, 2006.
    • Accepted December 6, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Michael Holinstat, Bryan Voss, Matthew L. Bilodeau and Heidi E. Hamm
Molecular Pharmacology March 1, 2007, 71 (3) 686-694; DOI: https://doi.org/10.1124/mol.106.029371

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Research ArticleArticle

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Michael Holinstat, Bryan Voss, Matthew L. Bilodeau and Heidi E. Hamm
Molecular Pharmacology March 1, 2007, 71 (3) 686-694; DOI: https://doi.org/10.1124/mol.106.029371
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