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

Abstract

Thromboxane A2 (TXA2)-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 PI3Kgamma 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 PI3Kgamma 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.

• Authors: Zhenyu Li, Guoying Zhang, Guy C Le Breton, Xiaopei Gao, Asrar B Malik, Xiaoping Du
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 33 Pg. 30725-31 (Aug 15 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12796499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Integrins
• Proto-Oncogene Proteins
• Receptors, Thromboxane
• Vasoconstrictor Agents
• Adenosine Diphosphate
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Adenosine Diphosphate (metabolism, pharmacology)
• Animals
• Blood Platelets (drug effects, enzymology, metabolism)
• Humans
• Integrins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation (drug effects)
• Platelet Aggregation (drug effects, physiology)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Receptors, Thromboxane (metabolism)
• Vasoconstrictor Agents (pharmacology)