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

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  • Simon Stritt

    (Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
    Rudolf Virchow Centre, 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
    Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France)

  • Remi Favier

    (Assistance Publique—Hôpitaux de Paris, Haematological Laboratory, Armand Trousseau Children Hospital, 26 Avenue du Docteur Arnold-Netter, 75012 Paris, France
    Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France)

  • Marie Favier

    (Inserm U1170, Gustave Roussy, University Paris Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France
    Inra, UMR_INRA 1260, 27 Boulevard Jean Moulin, 13385 Marseille, France
    Aix Marseille Université, 58 Boulevard Charles Livon, 13284 Marseille, France
    Inserm UMR_S 1062, 27 Boulevard Jean Moulin, 13385 Marseille, 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
    Rudolf Virchow Centre, 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
    Rudolf Virchow Centre, 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
    Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA)

  • Ernest Turro

    (University of Cambridge, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK
    NHS Blood and Transplant, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 0S, UK
    Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Robinson Way, Cambridge CB2 0SR, UK
    NIHR BioResource—Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Hills Rd, Cambridge CB2 0QQ, 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
    Imperial College Healthcare NHS Trust)

  • 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
    Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Max-Lebsche-Platz 31, 81377 Munich, Germany
    DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Lazarettstraße 36, 80636 Munich, Germany)

  • Bernhard Nieswandt

    (Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany
    Rudolf Virchow Centre, 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
    Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany)

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.

Suggested Citation

  • 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 & Stephan, 2016. "Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11097
    DOI: 10.1038/ncomms11097
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    Cited by:

    1. Kirill D. Nadezhdin & Leonor Correia & Chamali Narangoda & Dhilon S. Patel & Arthur Neuberger & Thomas Gudermann & Maria G. Kurnikova & Vladimir Chubanov & Alexander I. Sobolevsky, 2023. "Structural mechanisms of TRPM7 activation and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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