Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 36, Pages 26665-26674Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M602174200
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Funding
- NEI NIH HHS [EY010291, R01 EY010291] Funding Source: Medline
- NHLBI NIH HHS [F32 HL082068, HL-082068-01, F32 HL082068-01, HL084388, HL-076133-02, T32 HL076133, R01 HL084388] Funding Source: Medline
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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 P2Y(12) 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 PAR4-mediated aggregation are independent of calcium mobilization. Furthermore, we show that P2Y(12) 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. P2Y(12) 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.
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