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J. Biol. Chem., Vol. 279, Issue 44, 45354-45359, October 29, 2004

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Unresponsiveness of Platelets Lacking Both G_q and G₁₃

IMPLICATIONS FOR COLLAGEN-INDUCED PLATELET ACTIVATION^*

Alexandra Moers, Nina Wettschureck, Sabine Grüner, Bernhard Nieswandt, and Stefan Offermanns¶

From the Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany, and Rudolf-Virchow-Zentrum für Experimentelle Biomedizin, Versbacher St. 9, 97078 Würzburg, Germany

The diffusible platelet stimuli ADP and thromboxane A₂ activate multiple G protein-mediated signaling pathways and function as important secondary mediators of platelet activation as they are released from activated platelets. Because they can also increase their own formation and release, their effects are amplified; eventually, all major G protein-mediated signaling pathways are activated. The multiple positive feedback mechanisms operating during platelet activation have obscured the exact analysis of the roles individual G protein-mediated signaling pathways play during the platelet activation process. In this report, we show that platelets lacking G_q and G₁₃ are completely unresponsive to diffusible stimuli such as ADP, thromboxane A₂, or thrombin, even when applied at very high concentrations in combination, whereas all stimuli are able to induce platelet aggregation, shape change, and RhoA activation in platelets lacking only one G subunit. This shows that G_q or G₁₃ is required to induce some platelet activation, whereas the activation of G_i-mediated signaling alone is not sufficient to induceactivation of mouse platelets. In addition, platelets lacking G_q and G₁₃ adhered normally to collagen under high shearbut did not aggregate any more in response to collagen, indicating that collagen-induced platelet activation but not platelet adhesion requires intact G protein-mediated signaling pathways.

Received for publication, August 5, 2004 , and in revised form, August 18, 2004.

^* This study was funded by the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-6221-548246; Fax: 49-6221-548549; E-mail: stefan.offermanns{at}urz.uniheidelberg.de.

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