A platelet secretion pathway mediated by cGMP-dependent protein kinase.
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.
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA.
Zhenyu
Z
Li
Guoying
G
Zhang
Jasna Ajdic
JA
Marjanovic
Changgeng
C
Ruan
Xiaoping
X
Du
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000096:biosynthesis; D015539:Platelet Activation; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature
D004791:Enzyme Inhibitors; D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D002118:Calcium