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A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity
Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
University of Linköping, Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology.
Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping.
Department of Physiology, Eberhard Karls University, Tübingen, Germany.
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2012 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, 1743-52 p.Article in journal (Refereed) Published
Abstract [en]

Platelet aggregation, secretion and thrombus formation play a critical role in primary hemostasis to prevent excessive blood loss. On the other hand, uncontrolled platelet activation leads to pathological thrombus formation resulting in myocardial infarction or stroke. Stimulation of heterotrimeric G-proteins by soluble agonists or immunoreceptor tyrosine based activation motif-coupled receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI lead to the activation of phospholipases that cleave membrane phospholipids to generate soluble second messengers. Platelets contain the phospholipases (PL) D1 and D2 which catalyze the hydrolysis of phosphatidylcholine to generate the second messenger phosphatidic acid (PA). The production of PA is abrogated by primary alcohols that have been widely used for the analysis of PLD-mediated processes. However, it is not clear if primary alcohols effectively reduce PA generation or if they induce PLD-independent cellular effects. In the present study we made use of the specific PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and show for the first time, that FIPI enhances platelet dense granule secretion and aggregation of human platelets. Further, FIPI has no effect on cytosolic Ca(2+) activity but needs proper Rho kinase signaling to mediate FIPI-induced effects on platelet activation. Upon FIPI treatment the phosphorylation of the PKC substrate pleckstrin was prominently enhanced suggesting that FIPI affects PKC-mediated secretion and aggregation in platelets. Similar effects of FIPI were observed in platelets from mouse wild-type and Pld1(-/-) mice pointing to a new role for PLD2 as a negative regulator of platelet sensitivity.

Place, publisher, year, edition, pages
New York, USA: Elsevier, 2012. Vol. 24, no 9, 1743-52 p.
Keyword [en]
PLD, platelets, secretion, aggregation, regulation
National Category
Pharmacology and Toxicology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-42401DOI: 10.1016/j.cellsig.2012.04.018ISI: 000306621000003PubMedID: 22579635Scopus ID: 2-s2.0-84862656303OAI: oai:DiVA.org:oru-42401DiVA: diva2:786036
Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2017-10-17Bibliographically approved

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