Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases

Zhenyu Li, Guoying Zhang, Guy C. Le Breton, Xiaopei Gao, Asrar B. Malik, Xiaoping Du

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

Thromboxane A2 (TX2)-mediated platelet secretion and aggregation are important in thrombosis. Here, we present a novel finding that the stable TXA2 analogue, U46619, induces two waves of platelet secretion, each of which precedes a distinct wave of platelet aggregation. ADP released from platelets during the first wave of secretion played a major role in augmenting the first wave of platelet aggregation. The second wave of platelet secretion and aggregation required the first wave of both ADP secretion and aggregation and were blocked by either the integrin inhibitor RGDS or a P2Y12 receptor antagonist, indicating a requirement for both the integrin outside-in signal and ADP-activated Gi pathway. U46619 stimulated phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt, which was augmented by ADP but did not require integrin outside-in signaling. Platelets from PI3Kγ knock-out mice or PI3K inhibitor-treated platelets showed an impaired second wave of platelet secretion and aggregation. However, the second wave of platelet aggregation was restored by addition of exogenous ADP to PI3Kγ deficient or PI3K inhibitor-treated platelets. Thus, our data indicate that PI3K, together with the integrin outside-in signaling, play a central role in inducing the second wave of platelet secretion, which leads to the second wave of irreversible platelet aggregation.

Original languageEnglish
Pages (from-to)30725-30731
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number33
DOIs
StatePublished - Aug 15 2003

Funding

FundersFunder number
National Heart, Lung, and Blood Institute (NHLBI)R29HL052547

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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