1. Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.
- Author
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Stritt S, Nurden P, Favier R, Favier M, Ferioli S, Gotru SK, van Eeuwijk JM, Schulze H, Nurden AT, Lambert MP, Turro E, Burger-Stritt S, Matsushita M, Mittermeier L, Ballerini P, Zierler S, Laffan MA, Chubanov V, Gudermann T, Nieswandt B, and Braun A
- Subjects
- Animals, Blood Platelets metabolism, Humans, Megakaryocytes metabolism, Mice, Mutant Proteins metabolism, Nonmuscle Myosin Type IIA metabolism, Protein Serine-Threonine Kinases deficiency, TRPM Cation Channels deficiency, Thrombocytopenia metabolism, Thrombocytopenia pathology, Cytoskeleton metabolism, Homeostasis, Magnesium metabolism, Protein Serine-Threonine Kinases metabolism, TRPM Cation Channels metabolism, Thrombopoiesis
- 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.
- Published
- 2016
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