The human platelet is a major participant, normally and pathophysiologically, in coagulation and thrombosis, and can affect the contractile response of vascular tissue. Platelets also contribute to the formation of arterial plaques. Activation of platelet is dependent upon Ca-2-+ mobilization and secretion of material in platelet storage granules. Stimulated platelets display very rapid and marked alterations in phosphoinositide metabolism prior to Ca-2-+ mobilization and secretion. Increasing evidence indicate that breakdown of phosphoinositides (PtdIns, PtdIns4,5P-2) by phospholipase C (PLC) causes the mobilization of Ca-2-+ via myoinositol trisphosphate (IP-3), and activation of kinase by diacylglycerol (DG), which promote platelet morphological changes. Conversic of released arachidonic acid to prostaglandin metabolites can also participate in such activation of PLC. Utilizing techniques of capillary gas chromatography, electrophoresis, thin layer, ion exchange, and high pressure liquid chromatographies, as well as high voltage membrane permeabilization, all routinely performed in our laboratory, we will address the following questions: 1) How is PLC regulated? 2) Is the action of PLC on phosphatidylinositol (PtdIns) dependent upon hydrolysis of PtdIns4,5P-2? 3) What is the function of IP-3 in platelets? 4) Does epinephrine potentiate prostaglandin-related phosphoinositide metabolism? 5) Why is thrombin a more effective agonist for arachidonic acid release than is the prostaglandin H-2/thromboxane A-2 analogue U46619? Clarification of the factors (and their mechanisms of action) that affect phosphoinositide turnover and elucidation of the synergistic activation of platelets by epinephrine should enhance our understanding of events controlling platelet function in normal and pathological states.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hematology Subcommittee 2 (HEM)
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University of Vermont & St Agric College
Schools of Medicine
United States
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Zhang, Jin; Vanhaesebroeck, Bart; Rittenhouse, Susan E (2002) Human platelets contain p110delta phosphoinositide 3-kinase. Biochem Biophys Res Commun 296:178-81
Jin, Jianguo; Quinton, Todd M; Zhang, Jin et al. (2002) Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors. Blood 99:193-8
Banfic, H; Tang, X; Batty, I H et al. (1998) A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets. J Biol Chem 273:13-6
Zhang, J; Banfic, H; Straforini, F et al. (1998) A type II phosphoinositide 3-kinase is stimulated via activated integrin in platelets. A source of phosphatidylinositol 3-phosphate. J Biol Chem 273:14081-4
Banfic, H; Downes, C P; Rittenhouse, S E (1998) Biphasic activation of PKBalpha/Akt in platelets. Evidence for stimulation both by phosphatidylinositol 3,4-bisphosphate, produced via a novel pathway, and by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:11630-7
Domin, J; Pages, F; Volinia, S et al. (1997) Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J 326 ( Pt 1):139-47
Abrams, C S; Zhang, J; Downes, C P et al. (1996) Phosphopleckstrin inhibits gbetagamma-activable platelet phosphatidylinositol-4,5-bisphosphate 3-kinase. J Biol Chem 271:25192-7
Zhang, J; Zhang, J; Shattil, S J et al. (1996) Phosphoinositide 3-kinase gamma and p85/phosphoinositide 3-kinase in platelets. Relative activation by thrombin receptor or beta-phorbol myristate acetate and roles in promoting the ligand-binding function of alphaIIbbeta3 integrin. J Biol Chem 271:6265-72
Rittenhouse, S E (1996) Phosphoinositide 3-kinase activation and platelet function. Blood 88:4401-14
Zhang, J; Falck, J R; Reddy, K K et al. (1995) Phosphatidylinositol (3,4,5)-trisphosphate stimulates phosphorylation of pleckstrin in human platelets. J Biol Chem 270:22807-10

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