title: Reciprocal regulation of human platelet function by endogenous prostanoids and through multiple prostanoid receptors.
abstract: 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 PGE2 on platelets by functional responses and phosphorylation events. PGE2 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 PGE2 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.
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hubertus
authors.affiliation: Institut für Physik, University of Freiburg, Freiburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Mischnik
authors.affiliation: Institut für Physik, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Mark
authors.affiliation: BioCytex, Marseille, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Moulard
authors.affiliation: Center for Thrombosis & Haemostasis, Universitätsklinikum der Johannes Gutenberg-Universität Mainz, Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany; Interdisciplinary Bank of Biomaterials and Data Wuerzburg, Straubmuehlweg 2a, 97078 Wuerzburg, Germany. Electronic address: Joerg.Geiger@uni-wuerzburg.de.
authors.forename: Joerg
authors.initials: J
authors.lastname: Geiger
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D019007:P-Selectin; D010750:Phosphoproteins; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D000098662:Vasodilator-Stimulated Phosphoprotein; D012701:Serotonin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D020929:Mitogen-Activated Protein Kinase Kinases; D020827:rap1 GTP-Binding Proteins; D002118:Calcium
keywords: BW245c (CID 119304); BW868C (CID 57340013); CAY 10441 (CID 9839644); Cyclic AMP; L161,982 (CID 9961192); L798,106 (CID 15551229); P2Y12; Prostaglandin A1; Prostaglandin E2-synthase; Secretion; U46619 (CID 5311493); VASP; butaprost (CID 5311035); cangrelor (CID 9854012); iloprost (CID 5311181); prostaglandin A(1) (CID 5281912); prostaglandin D(2) (CID 448457); prostaglandin E(1) (CID 5280723); prostaglandin E(2) (CID 5280360); sulprostone (CID 5312153)