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首页> 外文期刊>Journal of Molecular Biology >TRPM7 activates m-calpain by stress-dependent stimulation of p38 MAPK and c-Jun N-terminal kinase.
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TRPM7 activates m-calpain by stress-dependent stimulation of p38 MAPK and c-Jun N-terminal kinase.

机译：TRPM7通过p38 MAPK和c-Jun N末端激酶的应激依赖性刺激来激活m-calpain。

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摘要

TRPM7 is a Ca(2)(+)-permeant and Mg(2)(+)-permeant ion channel in possession of its own kinase domain. In a previous study, we showed that overexpression of the channel-kinase in HEK-293 cells produced cell rounding and loss of adhesion, which was dependent on the Ca(2+)-dependent protease m-calpain. The TRPM7-elicited change in cell morphology was channel-dependent and occurred without any significant increase in cytosolic Ca(2+). Here we demonstrate that overexpression of TRPM7 increased levels of cellular reactive oxygen species (ROS) and nitric oxide, causing the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Application of inhibitors of p38 MAPK and JNK blocked TRPM7-induced cell rounding and activation of m-calpain, without affecting the phosphorylation state of the protease. Overexpression of TRPM7 increased intracellular Mg(2+); however, when the concentration of either external Ca(2+) or Mg(2+) was increased to favor the permeation of one divalent cation over the other, a similar increase in cell rounding and calpain activity was detected, indicating that TRPM7-mediated activation of m-calpain is not dependent on the nature of the divalent conducted by the channel. Application of inhibitors of nitric oxide synthase and mitochondrial-derived ROS reduced TRPM7-induced increases in nitric oxide and ROS production, blocked the change in cell morphology, and reduced cellular calpain activity. Collectively, our data reveal that excessive TRPM7 channel activity causes oxidative and nitrosative stresses, producing cell rounding mediated by p38 MAPK/JNK-dependent activation of m-calpain.
机译：TRPM7是一个拥有自己的激酶结构域的Ca（2）（+）渗透性和Mg（2）（+）渗透性离子通道。在以前的研究中，我们显示过激酶在HEK-293细胞中的过度表达会导致细胞变圆和粘附丧失，这取决于Ca（2+）依赖性蛋白酶m-钙蛋白酶。 TRPM7引起的细胞形态变化是通道依赖性的，发生时胞质Ca（2+）没有任何明显增加。在这里，我们证明TRPM7的过表达增加了细胞活性氧（ROS）和一氧化氮的水平，从而引起p38丝裂原活化蛋白激酶（MAPK）和c-Jun N端激酶（JNK）的激活。 p38 MAPK和JNK抑制剂的应用可阻断TRPM7诱导的细胞圆化和m-钙蛋白酶的活化，而不会影响蛋白酶的磷酸化状态。 TRPM7的过表达增加细胞内Mg（2+）;但是，当外部Ca（2+）或Mg（2+）的浓度增加以利于一个二价阳离子的渗透超过另一种时，则检测到细胞变圆和钙蛋白酶活性也有类似的升高，表明TRPM7介导间钙蛋白酶的激活不取决于该通道传导的二价的性质。一氧化氮合酶和线粒体来源的ROS抑制剂的应用减少了TRPM7诱导的一氧化氮和ROS产生的增加，阻止了细胞形态的变化，并降低了细胞钙蛋白酶的活性。总体而言，我们的数据表明，过度的TRPM7通道活性会引起氧化和亚硝化应激，从而产生由p38 MAPK / JNK依赖性m-钙蛋白酶激活介导的细胞变圆。

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