The MARCKS protein amount is differently regulated by calpain during toxic effects of methylmercury between SH-SY5Y and EA.hy926 cells.
The MARCKS protein amount is differently regulated by calpain during toxic effects of methylmercury between SH-SY5Y and EA.hy926 cells.
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DOI：
10.1292/jvms.17-0473
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发表时间：
2017-12-06
期刊：
影响因子：
--
通讯作者：
Miyamoto A
中科院分区：
文献类型：
--
作者：
Dao CV;Shiraishi M;Miyamoto A
甲基汞（MeHg）是一种对人类和动物具有严重毒性的环境污染物。然而，介导甲基汞毒性的分子机制尚未完全了解。我们以前曾报道，MARCKS蛋白参与甲基汞毒性SH-SY 5 Y神经母细胞瘤和EA.hy926血管内皮细胞系。此外，钙蛋白酶，钙依赖性蛋白酶，被认为是与甲基汞毒性。由于MARCKS是钙蛋白酶的底物，因此我们研究了钙蛋白酶激活和MARCKS切割之间的关系及其在MeHg毒性中的作用。在SH-SY 5 Y细胞中，甲基汞降低细胞活力沿着增加的钙动员，钙蛋白酶激活和MARCKS量减少。然而，用钙蛋白酶抑制剂预处理仅减弱了1 μM甲基汞诱导的细胞活力和MARCKS含量的降低，而3 μM甲基汞则没有。在MARCKS敲低的细胞中，钙蛋白酶抑制剂未能减弱甲基汞引起的细胞活力下降。在EA.hy926细胞，虽然甲基汞引起钙动员和MARCKS水平下降，钙蛋白酶激活没有观察到。这些结果表明，钙蛋白酶的参与调节MARCKS量依赖于细胞类型和甲基汞的浓度。在SH-SY 5 Y细胞中，钙蛋白酶介导的MARCKS蛋白水解参与低浓度甲基汞诱导的细胞毒性。
Methylmercury (MeHg) is an environmental pollutant that shows severe toxicity to humans and animals. However, the molecular mechanisms mediating MeHg toxicity are not completely understood. We have previously reported that the MARCKS protein is involved in the MeHg toxicity to SH-SY5Y neuroblastoma and EA.hy926 vascular endothelial cell lines. In addition, calpain, a Ca2+-dependent protease, is suggested to be associated with the MeHg toxicity. Because MARCKS is known as a substrate of calpain, we studied the relation between calpain activation and cleavage of MARCKS and its role in MeHg toxicity. In SH-SY5Y cells, MeHg decreased cell viability along with increased calcium mobilization, calpain activation and a decrease in MARCKS amounts. However, pretreatment with calpain inhibitors attenuated the decrease in cell viability and MARCKS amount induced only by 1 µM but not by 3 µM MeHg. In cells with a MARCKS knockdown, calpain inhibitors failed to attenuate the decrease in cell viability caused by MeHg. In EA.hy926 cells, although MeHg caused calcium mobilization and a decrease in MARCKS levels, calpain activation was not observed. These results indicate that the participation of calpain in the regulation of MARCKS amounts is dependent on the cell type and concentration of MeHg. In SH-SY5Y cells, calpain-mediated proteolysis of MARCKS is involved in cytotoxicity induced by a low concentration of MeHg.
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