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A dual thrombin receptor system for platelet activation

Nature volume 394, pages 690–694 (1998)Cite this article

Abstract

Platelet-dependent arterial thrombosis triggers most heart attacks and strokes. Because the coagulation protease thrombin is the most potent activator of platelets1, identification of the platelet receptors for thrombin is critical for understanding thrombosis and haemostasis. Protease-activated receptor-1 (PAR1) is important for activation of human platelets by thrombin2,3,4,5,6, but plays no apparent role in mouse platelet activation7,8,9. PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes10. Here we report that thrombin responses in platelets from PAR3-deficient mice were markedly delayed and diminished but not absent. We have also identified PAR4, a new thrombin-activated receptor. PAR4 messenger RNA was detected in mouse megakaryocytes and a PAR4-activating peptide caused secretion and aggregation of PAR3-deficient mouse platelets. Thus PAR3 is necessary for normal thrombin responses in mouse platelets, but a second PAR4-mediated mechanism for thrombin signalling exists. Studies with PAR-activating peptides suggest that PAR4 also functions in human platelets, which implies that an analogous dual-receptor system also operates in humans. The identification of a two-receptor system for platelet activation by thrombin has important implications for the development of antithrombotic therapies.

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Figure 1: Generation of PAR3-deficient mice.
Figure 2: Thrombin responses in PAR3-deficient platelets.
Figure 3: PAR4 amino-acid sequence and signalling properties.
Figure 4: Expression of PAR4 in mouse megakaryocytes and evidence for PAR4 function in mouse and human platelets.

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Acknowledgements

We thank T. Yu for blastocyst injection and H. Bourne for critical reading of this manuscript and S. E. Millar for assistance with figures.

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Authors and Affiliations

  1. Cardiovascular Research Institute and Daiichi Research Center, Box 0130, 505 Parnassus Avenue, San Francisco, 94143-0130, California, USA

    Mark L. Kahn, Yao-Wu Zheng, Wei Huang, Violeta Bigornia, Dewan Zeng, Stephen Moff, Carmen Tam & Shaun R. Coughlin

  2. Department of Medicine, Box 0130, 505 Parnassus Avenue, San Francisco, 94143-0130, California, USA

    Mark L. Kahn, Robert V. Farese Jr & Shaun R. Coughlin

  3. Gladstone Institute of Cardiovascular Disease, Box 0130, 505 Parnassus Avenue, San Francisco, 94143-0130, California, USA

    Robert V. Farese Jr

  4. Department of Cellular and Molecular Pharmacology, University of California, Box 0130, 505 Parnassus Avenue, San Francisco, 94143-0130, California, USA

    Shaun R. Coughlin

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  1. Mark L. Kahn
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Correspondence to Shaun R. Coughlin.

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Kahn, M., Zheng, YW., Huang, W. et al. A dual thrombin receptor system for platelet activation. Nature 394, 690–694 (1998). https://doi.org/10.1038/29325

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