Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 740, Issue -, Pages 15-27Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2014.06.030
Keywords
Prostaglandin A1; Prostaglandin E2-synthase; Secretion; Cyclic AMP; VASP; P2Y12
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Platelets are permanently exposed to a variety of prostanoids formed by blood cells or the vessel wall. The two major prostanoids, prostacyclin and thromboxane act through well established pathways mediated by their respective G-protein coupled receptors inhibiting or promoting platelet aggregation accordingly. Yet the role of other prostanoids and prostanoid receptors for platelet function regulation has not been thoroughly investigated. We aimed at a comprehensive analysis of prostanoid effects on platelets, the receptors and pathways involved and functional consequences. We analyzed cAMP formation and phosphorylation of proteins pivotal to platelet function as well as functional platelet responses such as secretion, aggregation and phosphorylation. The types of prostanoid receptors contributing and their individual share in signaling pathways were analyzed and indicated a major role for prostanoid IP1 and DP1 receptors followed by prostanoid EP4 and EP3 receptors while prostanoid EP2 receptors appear less relevant. We could show for the first time the reciprocal action of the endogenous prostaglandin PGE(2) on platelets by functional responses and phosphorylation events. PGE(2) evokes stimulatory as well as inhibitory effects in a concentration dependent manner in platelets via prostanoid EP3 or EP4 and prostanoid DP1 receptors. A mathematical model integrating the pathway components was established which successfully reproduces the observed platelet responses. Additionally we could show that human platelets themselves produce sufficient PGE(2) to act in an autocrine or paracrine fashion. These mechanisms may provide a fine tuning of platelet responses in the circulating blood by either promoting or limiting endogenous platelet activation. (C) 2014 Elsevier B.V. All rights reserved.
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