Abstract
The diffusible platelet stimuli ADP and thromboxane A(2) 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 G(13) are completely unresponsive to diffusible stimuli such as ADP, thromboxane A(2), 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 Galpha subunit. This shows that G(q) or G(13) 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 Galpha(q) and Galpha(13) 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.
Highlights
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
We show that platelets lacking Gq 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 indicates that platelet ADP receptors do not employ G␣13 and that platelet activation in response to ADP can be induced through Gq and Gi, which are activated by P2Y1 and P2Y12 receptors, respectively
Summary
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. We show that platelets lacking Gq 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 Gq or G13 is required to induce some platelet activation, whereas the activation of Gi-mediated signaling alone is not sufficient to induce activation of mouse platelets. Collagen is able to induce some platelet activation, the recruitment of additional platelets to the growing platelet plug involves the local accumulation of diffusable mediators, which are produced or released once platelet adhesion has been initiated and some level of activation through platelet adhesion receptors has occurred [6] These mediators include ADP/ATP and thromboxane A2 (TxA2) which are secreted or released from activated platelets as well as thrombin, which is produced on the surface of activated platelets. Our data show that collagen-induced activation of mouse platelets resulting in platelet aggregation and thrombus formation is completely dependent on intact G protein-mediated signaling pathways
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