CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells.
CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells.
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DOI：
10.1371/journal.pbio.3001496
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发表时间：
2021-12
期刊：
影响因子：
9.8
通讯作者：
Runnels LW
中科院分区：
文献类型：
--
作者：
Bai Z;Feng J;Franken GAC;Al'Saadi N;Cai N;Yu AS;Lou L;Komiya Y;Hoenderop JGJ;de Baaij JHF;Yue L;Runnels LW
镁是细胞生命所必需的，但它是如何稳态控制仍然知之甚少。在这里，我们报告说，CNNM家族的成员，这一直是有争议的牵连在细胞Mg 2+流入和流出，选择性结合TRPM 7通道，刺激二价阳离子进入细胞。CNNM与通道的共表达显著增加了二价阳离子的摄取，这是通过对通道孔的失活突变来防止的。敲除（KO）细胞中的TRPM 7或TRPM 7通道抑制剂NS 8593的应用也干扰CNNM刺激的二价阳离子摄取。相反，在HEK-293细胞中，CNNM 3和CNNM 4的KO显著降低TRPM 7介导的二价阳离子进入，而不影响TRPM 7蛋白表达或其细胞表面水平。此外，我们发现，细胞过度表达的磷酸酶再生肝（PRL），已知的CNNMs的结合伙伴，刺激TRPM 7依赖的二价阳离子进入和CNNMs需要这种活动。全细胞电生理记录表明，从HEK-293细胞中删除CNNM 3和CNNM 4会干扰异源表达和天然TRPM 7通道功能。我们得出结论，CNNM采用TRPM 7通道介导二价阳离子流入，CNNM还具有独立的TRPM 7-独立的Mg 2+流出活动，有助于CNNM控制细胞Mg 2+稳态。镁是细胞生命所必需的，但它是如何稳态控制的？这项研究表明，CNNM家族的蛋白质与TRPM 7通道结合，刺激二价阳离子进入细胞，而不依赖于它们调节镁离子流出的功能。
Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here, we report that members of CNNM family, which have been controversially implicated in both cellular Mg2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Coexpression of CNNMs with the channel markedly increased uptake of divalent cations, which is prevented by an inactivating mutation to the channel’s pore. Knockout (KO) of TRPM7 in cells or application of the TRPM7 channel inhibitor NS8593 also interfered with CNNM-stimulated divalent cation uptake. Conversely, KO of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry, without affecting TRPM7 protein expression or its cell surface levels. Furthermore, we found that cellular overexpression of phosphatases of regenerating liver (PRLs), known CNNMs binding partners, stimulated TRPM7-dependent divalent cation entry and that CNNMs were required for this activity. Whole-cell electrophysiological recordings demonstrated that deletion of CNNM3 and CNNM4 from HEK-293 cells interfered with heterologously expressed and native TRPM7 channel function. We conclude that CNNMs employ the TRPM7 channel to mediate divalent cation influx and that CNNMs also possess separate TRPM7-independent Mg2+ efflux activities that contribute to CNNMs’ control of cellular Mg2+ homeostasis. Magnesium is essential for cellular life, but how is it homeostatically controlled? This study shows that proteins of the CNNM family bind to the TRPM7 channel to stimulate divalent cation entry into cells, independent of their function in regulating magnesium ion efflux.
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影响因子：
4.6
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通讯作者：
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Tremblay, M. L.
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