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


0026-895X/07/7105-1399-1406$20.00
Mol Pharmacol 71:1399-1406, 2007

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PAR1, but Not PAR4, Activates Human Platelets through a Gi/o/Phosphoinositide-3 Kinase Signaling Axis

Bryan Voss, Joseph N. McLaughlin, Michael Holinstat, Roy Zent, and Heidi E. Hamm

Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (B.V., M.H., H.E.H.); Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois (J.N.M.); and Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Hospital, Nashville, Tennessee (R.Z.)

Thrombin-mediated activation of platelets is critical for hemostasis, but the signaling pathways responsible for this process are not completely understood. In addition, signaling within this cascade can also lead to thrombosis. In this study, we have defined a new signaling pathway for the thrombin receptor protease activated receptor-1 (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}IIbbeta3 activation and 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 P2Y purinoceptor 12, as an antiplatelet/antithrombotic drug, our data suggest that specifically blocking only PAR1-mediated Gi/o signaling could also be an effective therapeutic approach with the possibility of less unwanted bleeding.


Received December 11, 2006; accepted February 15, 2007

Address correspondence to: Heidi E. Hamm, Vanderbilt University Medical Center, 23rd Avenue South & Pierce, 442 Robinson Research Building, Nashville, TN 37232-6600. E-mail: heidi.hamm{at}vanderbilt.edu







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