A key role for Mg(2+) in TRPM7's control of ROS levels during cell stress.
A key role for Mg(2+) in TRPM7's control of ROS levels during cell stress.
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Mg(2+) 在细胞应激期间 TRPM7 控制 ROS 水平中发挥关键作用。
DOI：
10.1042/bj20120248
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发表时间：
2012-08-01
期刊：
影响因子：
--
通讯作者：
Runnels LW
中科院分区：
文献类型：
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作者：
Chen HC;Su LT;González-Pagán O;Overton JD;Runnels LW
TRPM 7通道已被证明在脑缺血期间的细胞存活中以及在受到凋亡刺激的其他细胞类型的存活中起关键作用。Ca 2+被认为是该通道调节活性氧（ROS）产生的能力的核心。然而，通道介导的Mg 2+和Zn 2+的进入也与细胞死亡有关。在这里，我们表明，在成纤维细胞中的RNA干扰TRPM 7的耗竭增加细胞对细胞凋亡刺激的抗性，通过降低ROS水平在Mg 2+依赖性的方式。TRPM 7的缺失降低了细胞Mg 2+，降低了ROS的浓度，减少了p38 MAP激酶和JNK的活化，以及减少了响应于凋亡刺激的caspase-3活化和PARP裂解。TRPM 7或TRPM 7的激酶失活突变体在TRPM 7敲除细胞中的再表达增加了细胞Mg 2+和ROS水平，Mg 2+转运蛋白SLC 41 A2的表达也是如此。此外，SLC 41 A2的表达增加了TRPM 7敲低细胞对凋亡刺激的敏感性，并促进了响应细胞应激的ROS产生。这些数据共同揭示了Mg 2+在TRPM 7控制细胞存活和调节细胞ROS水平中的重要作用。
The TRPM7 channel has been shown to play a pivotal role in cell survival during brain ischemia as well as in the survival of other cell types challenged with apoptotic stimuli. Ca2+ is thought to be central to the channel’s ability to regulate reactive oxygen species (ROS) production. However, channel-mediated entry of Mg2+ and Zn2+ have also been implicated in cell death. Here we show that depletion of TRPM7 by RNA interference in fibroblasts increases cell resistance to apoptotic stimuli by decreasing ROS levels in a Mg2+-dependent manner. Depletion of TRPM7 lowered cellular Mg2+, decreased the concentration of ROS and lessened p38 MAP kinase and JNK activation as well as decreased caspase-3 activation and PARP cleavage in response to apoptotic stimuli. Re-expression of TRPM7 or of a kinase-inactive mutant of TRPM7 in TRPM7-knockdown cells increased cellular Mg2+ and ROS levels, as did expression of the Mg2+ transporter SLC41A2. In addition, expression of SLC41A2 increased TRPM7-knockdown cells’ sensitivity to apoptotic stimuli as well as boosted ROS generation in response to cell stress. Together these data uncover an essential role for Mg2+ in TRPM7’s control of cell survival and in the regulation of cellular ROS levels.