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

Stritt, Simon; Nurden, Paquita; Favier, Remi; Favier, Marie; Ferioli, Silvia; Gotru, Sanjeev K.; Eeuwijk, Judith M. M. van; Schulze, Harald; Nurden, Alan T.; Lambert, Michele P.; Turro, Ernest; Burger-Stritt, Stephanie; Matsushita, Masayuki; Mittermeier, Lorenz; Ballerini, Paola; Zierler, Susanna; Laffan, Michael A.; Chubanov, Vladimir; Gudermann, Thomas; Nieswandt, Bernhard und Braun, Attila (2016): Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture. In: Nature Communications, Bd. 7, 11097

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 alpha-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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Walther-Straub-Institut für Pharmakologie und Toxikologie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch