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Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.

Nature communications (2016-03-30)
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
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.

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