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

Simon Stritt,Lorenz Mittermeier,Attila Braun,Thomas Gudermann,Susanna Zierler,Stephanie Burger-Stritt,Masayuki Matsushita,Paola Ballerini,Alan T Nurden,Silvia Ferioli,Harald Schulze,Bernhard Nieswandt,Paquita Nurden,Ernest Turro,Vladimir Chubanov,Michele P Lambert,Maryline Favier ,Michael Laffan ,Rémi Favier ,Sanjeev Kiran Gotru ,Judith M.m Van Eeuwijk

doi:10.1038/ncomms11097

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.

Highlights

Mg2 þ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2 þ ]i in megakaryocytes (MKs) and platelets are largely unknown
These results demonstrate a critical role of Transient receptor potential melastatin-like 7 channel (TRPM7)-mediated Mg2 þ influx in regulating non-muscle myosin IIA heavy chain (NMMIIA) activity and cytoskeletal rearrangements during thrombopoiesis
It has been shown that Mg2 þ inhibits NMMIIA activity by reducing the ADP release rate and its affinity for actin[26]

Summary

Introduction

Mg2 þ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2 þ ]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 (TRPM7) channel and kinase domain, but not its kinase activity, are critical for embryonic development[4,5,6] and knockdown or cell-specific TRPM7 knockout approaches give rise to impaired cytoskeletal organization, cell migration, proliferation, polarization and survival. These defects could partially be explained by increased non-muscle myosin IIA heavy chain (NMMIIA)-mediated contractility of the actin cytoskeleton[5,7,8,9,10,11,12,13]. Our findings reveal TRPM7 dysfunction as a novel cause of macrothrombocytopenia in mice and potentially in humans too

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Results

Conclusion