Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.
Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture.
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TRPM7通道函数中的缺陷通过改变的细胞MG（2+）稳态和细胞骨架结构来消除血小板。
DOI：
10.1038/ncomms11097
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发表时间：
2016-03-29
影响因子：
16.6
通讯作者：
Braun A
中科院分区：
文献类型：
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作者：
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;Braun A
Mg2+在血小板功能中起着至关重要的作用，但尽管对中风或心肌梗死等危及生命的疾病有影响，但在巨核细胞（mk）和血小板中控制[Mg2+]i的机制在很大程度上是未知的。瞬时受体电位褪化抑素样7通道（TRPM7）是一种普遍存在的、具有组成性活性的阳离子通道，具有胞浆α-激酶结构域，对胚胎发育和细胞存活至关重要。在这里，我们报告了mk中TRPM7通道功能受损导致小鼠（Trpm7fl/fl-Pf4Cre）大量血小板减少症，并且可能在人类谱系的几个成员中，此外还患有房颤。血小板生物发生缺陷主要是由于细胞骨架改变导致Trpm7fl/fl-Pf4Cre mk的血小板前形成受损，通过补充Mg2+或化学抑制非肌肉肌球蛋白IIA重链活性来挽救。总的来说，我们的研究结果表明TRPM7功能障碍可能导致人类和小鼠的巨血小板减少症。尽管Mg2+对血小板的激活和聚集至关重要，但其在这些细胞中的调节作用仍在很大程度上未知。在这里，作者表明TRPM7，一种阳离子通道和蛋白激酶，通过影响小鼠和人类这些细胞的细胞骨架来调节血小板生成和血小板大小。
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. Although Mg2+ is vital for platelet activation and aggregation, its regulation in these cells is still largely unknown. Here, the authors show that TRPM7, a cation channel and a protein kinase, regulates thrombopoiesis and platelet size by affecting the cytoskeleton of these cells in mice and humans.