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J. Biol. Chem., Vol. 281, Issue 36, 26665-26674, September 8, 2006

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PAR4, but Not PAR1, Signals Human Platelet Aggregation via Ca²⁺ Mobilization and Synergistic P2Y₁₂ Receptor Activation^*

Michael Holinstat, Bryan Voss, Matthew L. Bilodeau, Joseph N. McLaughlin^¶, John Cleator, and Heidi E. Hamm¹

From the Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, the Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, and the ^¶Department of Pharmacology, University of Illinois, Chicago, Illinois 60608

Regulation of platelet activation plays a central role in hemostasis and pathophysiological processes such as coronary artery disease. Thrombin is the most potent activator of platelets. Human platelets express two thrombin receptors, PAR1 and PAR4, both of which signal platelet activation. Evidence is lacking on the mechanism by which PAR1 and PAR4 may differentially signal platelet aggregation. Here we show that at the relatively high concentration of agonist most likely found at the site of a local thrombus, dual inhibition of the P2Y₁₂ receptor and calcium mobilization result in a complete inhibition of PAR4-induced aggregation, while having no effect on either thrombin or PAR1-mediated platelet aggregation. Both PAR1- and PAR4mediated aggregation are independent of calcium mobilization. Furthermore, we show that P2Y₁₂ receptor activation is not required for protease-activated receptor-mediated aggregation at higher agonist concentrations and is only partially required for Rap1 as well as GPIIbIIIa activation. P2Y₁₂ receptor inhibitors clinically in use such as clopidogrel are postulated to decrease platelet aggregation through partial inhibition of PAR1 signaling. Our data, however, indicate that at high local concentrations of thrombin, it is the signaling through PAR4 rather than PAR1 that may be regulated through purinergic feedback. Thus, our data identify an intra-platelet mechanism that may function as a future site for therapeutic intervention.

Received for publication, March 7, 2006 , and in revised form, July 10, 2006.

^* This work was supported by National Institutes of Health Grants HL084388 and EY010291 (to H. E. H.) and National Research Service Awards HL-076133-02 and HL-082068-01 (to M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Vanderbilt University Medical Center, 23rd Ave. South and Pierce, 442 Robinson Research Bldg., Nashville, TN 37232-6600. Tel.: 615-343-3533; Fax: 615-343-1084; E-mail: heidi.hamm{at}vanderbilt.edu.

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