Stritt Simon, Nurden Paquita, Favier Remi, Favier Marie, Ferioli Silvia, Gotru Sanjeev K, van Eeuwijk Judith M M, Schulze Harald, Nurden Alan T, Lambert Michele P, Turro Ernest, Burger-Stritt Stephanie, Matsushita Masayuki, Mittermeier Lorenz, Ballerini Paola, Zierler Susanna, Laffan Michael A, Chubanov Vladimir, Gudermann Thomas, Nieswandt Bernhard, Braun Attila
Chair of Experimental Biomedicine, University Hospital, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
Rudolf Virchow Centre, University of Würzburg, Josef-Schneider-Strasse 2, 97078 Würzburg, Germany.
Nat Commun. 2016 Mar 29;7:11097. doi: 10.1038/ncomms11097.
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.
镁离子（Mg(2+)）在血小板功能中起着至关重要的作用，但尽管其对中风或心肌梗死等危及生命的疾病有影响，控制巨核细胞（MKs）和血小板中[Mg(2+)]i的机制在很大程度上仍不清楚。瞬时受体电位褪黑素样7通道（TRPM7）是一种普遍存在的、组成型活性阳离子通道，具有一个胞质α激酶结构域，对胚胎发育和细胞存活至关重要。在此，我们报告，MKs中TRPM7通道功能受损会导致小鼠出现大血小板减少症（Trpm7(fl/fl-Pf4Cre)），并且可能在一个人类家系的几名成员中出现，此外，这些成员还患有心房颤动。血小板生成缺陷主要由细胞骨架改变引起，导致Trpm7(fl/fl-Pf4Cre) MKs的前血小板形成受损，补充Mg(2+)或化学抑制非肌肉肌球蛋白IIA重链活性可挽救这一缺陷。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出现大血小板减少症。
