Role of phosphatidylinositol 3-kinase in platelet aggregation

Platelet aggregation plays an important role in haemostasis and vascular di sorders. This mainly takes place by the action of endogenous agonists like ADP, platelet-activating factor (PAF), epinephrine, 5-hydroxytryptamine (5- HT) and arachidonic acid (AA). These agonists except AA interact with G-pro tein coupled receptors Recent studies have shown that phosphatidylinositol 3-kinase (PI 3-kinase) and myosin light chain kinase (MLCK) play an importa nt role in platelet aggregation We have shown that low doses of the selecti ve PI 3-kinase inhibitor, wortmannin, inhibits aggregation (IC50; 20 nM) me diated by subthreshold doses of 5-hydroxytryptamine (5-HT; 5 mu M) and epin ephrine (1 mu M). This study was undertaken to examine the effects of wortm annin in platelet aggregation induced by various platelet agonists. The res ults show that wortmannin inhibited aggregation mediated by various agonist s with an IC50 for ADP (110 nM), AA (2 mu M), collagen (280 nM) and PAF (52 0 nhl). These studies suggest that wortmannin-mediated inhibition of aggreg ation induced by ADP, epinephrine, collagen and PAF may affect multiple enz ymatic pathways and the most likely targets seem to be both PI 3-kinase and MLCK as other kinases like cAMP- and calcium-calmodulin-dependent protein kinases are reported to be not affected by wortmannin.