Abstract
Platelet secretion (exocytosis) is critical in amplifying platelet activation, in stabilizing thrombi, and in arteriosclerosis and vascular remodeling. The signaling mechanisms leading to secretion have not been well defined. We have shown previously that cGMP-dependent protein kinase (PKG) plays a stimulatory role in platelet activation via the glycoprotein Ib-IX pathway. Here we show that PKG also plays an important stimulatory role in mediating aggregation-dependent platelet secretion and secretion-dependent second wave platelet aggregation, particularly those induced via Gq-coupled agonist receptors, the thromboxane A2 (TXA2) receptor, and protease-activated receptors (PARs). PKG I knock-out mouse platelets and PKG inhibitor-treated human platelets showed diminished aggregation-dependent secretion and also showed a diminished secondary wave of platelet aggregation induced by a TXA2 analog and thrombin receptor-activating peptides that were rescued by the granule content ADP. Low dose collagen-induced platelet secretion and aggregation were also reduced by PKG inhibitors. Furthermore PKG I knockout and PKG inhibitors significantly attenuated activation of the Gi pathway that is mediated by secreted ADP. These data unveil a novel PKG-dependent platelet secretion pathway and a mechanism by which PKG promotes platelet activation.
Highlights
The secretion of granule contents is an important cellular function shared by blood platelets, leukocytes, neurons, endocrine glands, and many other cell types
PKG I knockout (Fig. 1A) or PKG inhibitors Rp-pCPT-cGMPS, KT5823 (Fig. 1C), or RpBr-PET-cGMPS significantly reduced platelet aggregation induced by U46619 but had no significant effect on platelet aggregation induced by ADP (Fig. 1D)
It has been believed for the past 30 years that the cGMP-PKG pathway inhibits platelet activation, we have shown recently that cGMP promotes glycoprotein Ib-IX (GPIb-IX)-dependent integrin activation and platelet aggregation
Summary
PKG Stimulates Platelet Exocytosis relatively high concentration of collagen but is required for inhibition of collagen-induced platelet activation by a high concentration of a cGMP analog [22] It is not clear whether PKG plays a role in platelet activation induced by GPIb-IXindependent, G-protein-coupled platelet agonists, which are critical in thrombus formation. We present a new finding that PKG is an important signaling mediator for aggregation-dependent secretion of platelet granules and that PKG-dependent secretion of dense granules is required in the second wave platelet aggregation induced by low doses of platelet agonists These findings define a novel signaling mechanism that is important in understanding the roles of PKG in platelet activation and has implications for understanding the common signaling mechanisms of degranulation and exocytosis
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