Tyrosine Phosphorylation and Syk Activation Are Involved in Thrombin-Induced Aggregation of Epinephrine-Potentiated Platelets

Abstract

Thrombin and epinephrine in combination exert synergistic effects on platelet activation. On the other hand, tyrosine phosphorylation and activation of tyrosine kinases including Syk have been shown to play a critical role in the induction of platelet responses to thrombin stimulation. This study investigated the role of tyrosine phosphorylation and Syk activation in the synergistic mechanisms between thrombin and epinephrine. Although epinephrine alone (4 microM) slightly induced protein-tyrosine phosphorylation and Syk activation, the presence of epinephrine caused a shift to the left in the dose-dependence of thrombin (0.01-0.5 U/ml)-induced tyrosine phosphorylation and Syk activation, as well as platelet aggregation. Phenoxybenzamine, an alpha-adrenoceptor antagonist, canceled this potentiation by epinephrine. Since platelets dominantly express alpha 2-adrenoceptor, this result indicates that epinephrine acts through the occupancy of alpha 2-adrenoceptor. Furthermore, pretreatment with a tyrosine kinase inhibitor, genistein, or a cAMP-elevating agent, prostacyclin (PGI2), significantly reduced these synergistic effects of epinephrine. Taken together, our results suggested that the potentiation by epinephrine may be mediated via enhancement of tyrosine phosphorylation and Syk activation, in part through a decrease of intracellular cAMP levels.

The ATP-gated P2X1 Receptor Plays a Pivotal Role in Activation of Aspirin-treated Platelets by Thrombin and Epinephrine

“…It has been proposed that decreased production of cyclic AMP and activation of Syk tyrosine kinase and PKC are important signaling events in the thrombin-epinephrine cross-talk (12,15). Our results imply that PKC activation is involved in the interaction between PAR1 and epinephrine.…”

“…From a mechanistic perspective, epinephrine has been found to potentiate the Ca 2ϩ mobilization induced by thrombin and other agonists (12). Activation of Syk tyrosine kinase, protein kinase C (PKC), and extracellular signal-regulated kinase 2 (ERK2) have also been implicated in the interaction between thrombin and other platelet activators (12)(13)(14)(15).…”

Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet aggregation through activation of phospholipase C and Ca2+ signalling pathways

“…In fact epinephrine effects in platelets may involve multiple signalling pathways; stimulation of IP 3 production through stimulation of PLC by G protein β γ-subunits (Clapham and Neer, 1997;Banno et al, 1998), increase in Ca 2+ -influx, thus activation of phospholipase A2 (Heemskerk and Sage, 1994) and activation of some other proteins like Syk (Wang et al ., 1997). In conclusion, our results point to a new facet of 5-HT and epinephrine synergistic interaction and further demonstrate that such an effect is receptor mediated and occurs due to activation of Gq and Gi proteins which converge at PLC and Ca 2 + s i gnalling pathways as depicted in Figure 4.…”

ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fcɛ receptor I-mediated activation of Syk

“…The results of this study demonstrate that ER-27319 inhibits all of the aforementioned events we studied, consistent with the inhibition of Syk by this compound. The critical role of Syk in cell activation is not restricted to mast cells and basophils but is also important to B cell and platelet function (30,31). In B cells, Syk activity is induced by its association with the Ig␣͞Ig␤ ITAMs (23).…”