Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture

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 () and Attila Braun ()
Additional contact information
Simon Stritt: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Paquita Nurden: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Remi Favier: Assistance Publique—Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France
Marie Favier: Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France
Silvia Ferioli: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany
Sanjeev K. Gotru: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Judith M M. van Eeuwijk: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Harald Schulze: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Alan T. Nurden: Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France
Michele P. Lambert: Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA
Ernest Turro: University of Cambridge, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK
Stephanie Burger-Stritt: Endocrinology and Diabetes Unit, University Hospital of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany
Masayuki Matsushita: Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Okinawa 903-0215, Japan
Lorenz Mittermeier: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany
Paola Ballerini: Assistance Publique—Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France
Susanna Zierler: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany
Michael A. Laffan: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, Du Cane Road, London SW7 2AZ, UK
Vladimir Chubanov: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany
Thomas Gudermann: Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestraße 33, 80336 Munich, Germany
Bernhard Nieswandt: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
Attila Braun: Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+]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 (Trpm7fl/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 Trpm7fl/fl-Pf4Cre MKs, which is rescued by Mg2+ 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.

Date: 2016
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DOI: 10.1038/ncomms11097

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