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Defective platelet activation in Gαq-deficient mice

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Abstract

Platelets are small disc-shaped cell fragments which undergo a rapid transformation when they encounter vascular damage. They become more spherical and extrude pseudopodia, their fibrinogen receptors are activated, causing them to aggregate, they release their granule contents, and eventually form a plug which is responsible for primary haemostasis1. Activation of platelets is also implicated in the pathogenesis of unstable angina, myocardial infarction and stroke2,3. Here we show that platelets from mice deficient in the α-subunit of the heterotrimeric guanine-nucleotide-binding protein Gq are unresponsive to a variety of physiological platelet activators. As a result, Gαq-deficient mice have increased bleeding times and are protected from collagen and adrenaline-induced thromboembolism. We conclude that Gαq is essential for the signalling processes used by different platelet activators and that it cannot be replaced by Gαi or the βγ subunits of the heterotrimeric G proteins. Gαq may thus be a new target for drugs designed to block the activation of platelets.

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Figure 1: Gα expression in wild-type and Gαq deficient mice.
Figure 2: Aggregation response of wild-type (WT) and Gαq-deficient (−/−) platelet-rich plasma.
Figure 3: Lack of InsP3 production and Ca2+ mobilization in Gαq-deficient platelets.
Figure 4: Haemostasis and thromboembolism.

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Acknowledgements

We thank S. R. Coughlin and H. Ishihara for advice, and V. Mancino, H. Li, S. Pease and J. Silva for technical help. S.O. was a recipient of a fellowship from the Deutsche Forschungsgemeinschaft and the Guenther Foundation. Supported by a grant from the NIH to M.I.S.

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Author notes

  1. Stefan Offermanns

    Present address: Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69–73, 14195, Berlin, Germany

Authors and Affiliations

  1. Division of Biology 147-75, California Institute of Technology, Pasadena, 91125, California, USA

    Yi-Hui Hu

  2. Department of Pharmacology, Amgen Inc., 1840 DeHavilland Drive, Thousand Oaks, 91320, California, USA

    Christopher F. Toombs & Melvin I. Simon

Author notes

  1. Melvin I. Simon: Correspondence and requests for materials should be addressed to M.I.S.

    • Melvin I. Simon
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Offermanns, S., Toombs, C., Hu, YH. et al. Defective platelet activation in Gαq-deficient mice. Nature 389, 183–186 (1997). https://doi.org/10.1038/38284

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