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Abstract
Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.
Highlights
Platelets play an important role in maintaining the vascular integrity and haemostasis
The second messengers, Ca2+ and protein kinase C (PKC) generated in response to Gq/phospholipase C (PLC) activation bring about coordinated changes leading towards platelet aggregation (Crabos et al, 1992; Heemskerk and Sage, 1994)
Since the synergism of these agonists was inhibited by indomethacin, a COX-1 inhibitor, it seems that the agonist-mediated synergism follows activation of COX-1 distal to PLC/Ca2+ activation
Summary
Abbreviations: (Ca2+); calcium, COX, cyclooxygenase; ERK1/2, extracellularly regulated mitogen-activated protein kinases; 5-HT, 5hydroxytryptamine; NO, nitric oxide; PAF, platelet-activating factor; PKC, protein kinase C; PLC, phospholipase C; PI 3-kinase, phosphatidylinositol 3-kinase; TXA2, thromboxane A2
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