Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture
Year: 2016
Type: article
Abstract: Mg(2+) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg(2+)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg(2+) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
Source: Nature Communications
DOI: 10.1038/ncomms11097
Authors: Simon Stritt, Paquita Nurden, Remi Favier, Marie Favier, Silvia Ferioli, Sanjeev K. Gotru, Judith M M. van Eeuwijk, Harald Schulze, Alan T. Nurden, Michele P. Lambert, Ernest Turro, Stephanie Burger-Stritt, Masayuki Matsushita, Lorenz Mittermeier, Paola Ballerini, Susanna Zierler, Michael A. Laffan, Vladimir Chubanov, Thomas Gudermann, Bernhard Nieswandt, Attila Braun
Institutions: University of Würzburg, Universitätsklinikum Würzburg, Centre Hospitalier Universitaire de Bordeaux, Electrophysiology and Heart Modeling Institute, Hôpital Xavier Arnozan, Plateforme Technologique d'Innovation Biomédicale, Inserm, Institut Gustave Roussy, Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Contrôle transcriptionnel et épigénétique de l’hématopoïèse maligne, Aix-Marseille Université, Nutrition, Obésité et Risque Thrombotique, Institut National de la Recherche Agronomique, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Children's Hospital of Philadelphia, University of Pennsylvania, NHS Blood and Transplant, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, MRC Biostatistics Unit, NIHR BioResource, Medical Research Council, University of the Ryukyus, Imperial College Healthcare NHS Trust, Imperial College London, German Centre for Cardiovascular Research, German Center for Lung Research
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W2313039228