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G_13 is an essential mediator of platelet activation in hemostasis and thrombosis

Moers, Alexandra and Nieswandt, Bernhard and Massberg, Steffen and Wettschureck, Nina and Grüner, Sabine and Konrad, Ildiko and Schulte, Valerie and Aktas, Barsom and Gratacap, Marie-Pierre and Simon, Melvin I. and Gawaz, Meinrad and Offermanns, Stefan (2003) G_13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nature Medicine, 9 (11). pp. 1418-1422. ISSN 1078-8956. doi:10.1038/nm943.

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Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A_2 (TXA_2) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G_q, G_i and G_z (refs. 4, 5, 6). However, the role and relative importance of G12 and G13, which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha_13, but not Galpha_12, severely reduced the potency of thrombin, TXA2 and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha_13 deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G_13-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.

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Additional Information:© 2003 Nature Publishing Group. Received 24 July; accepted 13 September 2003. We thank A. Rogatzki and A. Rippberger for expert technical help and B. Arnold for kind help with bone marrow transplantation experiments. This work was supported by the Deutsche Forschungsgemeinschaft and the Volkswagen Foundation.
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Deutsche Forschungsgemeinschaft (DFG)UNSPECIFIED
Volkswagen FoundationUNSPECIFIED
Issue or Number:11
Record Number:CaltechAUTHORS:20150513-095213359
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Official Citation:Moers, A., Nieswandt, B., Massberg, S., Wettschureck, N., Gruner, S., Konrad, I., . . . Offermanns, S. (2003). G13 is an essential mediator of platelet activation in hemostasis and thrombosis. [10.1038/nm943]. Nat Med, 9(11), 1418-1422.
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ID Code:57484
Deposited On:13 May 2015 21:14
Last Modified:10 Nov 2021 21:50

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