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

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 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 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.

• Stritt, S.
• Nurden, P.
• Favier, R.
• Favier, M.
• Ferioli, S.
• Gotru, S. K.
• van Eeuwijk, J. M.
• Schulze, H.
• Nurden, A. T.
• Lambert, M. P.
• Turro, E.
• Burger-Stritt, S.
• Matsushita, M.
• Mittermeier, L.
• Ballerini, P.
• Zierler, S.
• Laffan, M. A.
• Chubanov, V.
• Gudermann, T.
• Nieswandt, B.
• Braun, A.