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First published on February 15, 2007; DOI: 10.1124/mol.106.033365

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Received for publication December 12, 2006.
Revised February 2, 2007.
Accepted for publication February 15, 2007.

PAR1, but not PAR4, activates human platelets through a Gi/o/PI3K signaling axis

Bryan Voss 1, Joseph N McLaughlin 2, Michael Holinstat 1, Roy Zent 1, Heidi E. Hamm 3*

1 Vanderbilt University Medical Center 2 University of Illinois-Chicago 3 Vanderbilt University

* Address correspondence to: E-mail: heidi.hamm{at}vanderbilt.edu

Abstract

Thrombin-mediated activation of platelets is critical for hemostasis, but the signaling pathways responsible for this process are not completely understood. Additionally, signaling within this cascade can also lead to thrombosis. In this study we have defined a new signaling pathway for the thrombin receptor PAR1 in human platelets. We show that PAR1 couples to Gi/o in human platelets and activates phosphoinositide-3 kinase (PI3K). PI3K activation regulates platelet integrin {alpha}IIb{beta} (GPIIbIIIa) activation, platelet aggregation, and potentiates the PAR1-mediated increase in intraplatelet calcium concentration. PI3K inhibitors eliminated these effects downstream of PAR1, but they had no effect on PAR4 signaling. This study has identified an important role for the direct activation of Gi/o by PAR1 in human platelets. Given the efficacy of clopidogrel, which blocks the Gi/o coupled P2Y12 receptor, as an antiplatelet/antithrombotic drug, our data suggests that specifically blocking only PAR1-mediated Gi/o signaling could also be an effective therapeutic approach with the possibility of less unwanted bleeding.


Key words: Thrombin/PAR, Gi family, Calcium (G Protein Coupled Signals), Fluorescence techniques, Platelets


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S. M. Cifuni, D. D. Wagner, and W. Bergmeier
CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin {alpha}IIb{beta}3 in platelets
Blood, September 1, 2008; 112(5): 1696 - 1703.
[Abstract] [Full Text] [PDF]


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