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RhoA downstream of G(q) and G(12/13) pathways regulates protease-activated receptor-mediated dense granule release in

Jianguo Jin1, Yingying Mao, Dafydd Thomas

  • 1Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA.

Biochemical Pharmacology
|December 17, 2008
PubMed

Platelet secretion is an important physiological event in hemostasis. The protease-activated receptors, PAR 1 and PAR 4, and the thromboxane receptor activate the G(12/13) pathways, in addition to the G(q) pathways. Here, we investigated the contribution of G(12/13) pathways to platelet dense granule release. 2MeSADP, which does not activate G(12/13) pathways, does not cause dense granule release in aspirin-treated platelets. However, supplementing 2MeSADP with YFLLRNP (60muM), as selective activator of G(12/13) pathways, resulted in dense granule release. Similarly, supplementing PLC activation with G(12/13) stimulation also leads to dense granule release. These results demonstrate that supplemental signaling from G(12/13) is required for G(q)-mediated dense granule release and that ADP fails to cause dense granule release because the platelet P2Y receptors, although activate PLC, do not activate G(12/13) pathways. When RhoA, downstream signaling molecule in G(12/13) pathways, is blocked, PAR-mediated dense granule release is inhibited. Furthermore, ADP activated RhoA downstream of G(q) and upstream of PLC. Finally, RhoA regulated PKCdelta T505 phosphorylation, suggesting that RhoA pathways contribute to platelet secretion through PKCdelta activation. We conclude that G(12/13) pathways, through RhoA, regulate dense granule release and fibrinogen receptor activation in platelets.

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