期刊
JOURNAL OF NEUROCHEMISTRY
卷 119, 期 5, 页码 1108-1118出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07493.x
关键词
apoptosis; cadmium; calcium; calmodulin-dependent protein kinase II; calcium ion; mammalian target of rapamycin; mitogen-activated protein kinase
资金
- National Natural Science Foundation of China [30971486]
- Scientific Research Foundation of the State Education Ministry of China [SEMR20091341]
- Project for the Priority Academic Program Development
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [10KJA180027]
- NIH [CA115414]
- American Cancer Society [RSG-08-135-01-CNE]
- Louisiana Board of Regents [NSF-2009-PFUND-144]
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently, we have shown that Cd elevates intracellular free calcium ion ([Ca2+]i) level, leading to neuronal apoptosis partly by activating mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains to be elucidated. In this study, we show that the effects of Cd-elevated [Ca2+]i on MAPK and mTOR network as well as neuronal cell death are through stimulating phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). This is supported by the findings that chelating intracellular Ca2+ with 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester or preventing Cd-induced [Ca2+]i elevation using 2-aminoethoxydiphenyl borate blocked Cd activation of CaMKII. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of MAPK/mTOR pathways and cell death. Furthermore, inhibitors of mTOR (rapamycin), c-Jun N-terminal kinase (SP600125) and extracellular signal-regulated kinase 1/2 (U0126), but not of p38 (PD169316), prevented Cd-induced neuronal cell death in part through inhibition of [Ca2+]i elevation and CaMKII phosphorylation. The results indicate that Cd activates MAPK/mTOR network triggering neuronal cell death, by stimulating CaMKII. Our findings underscore a central role of CaMKII in the neurotoxicology of Cd, and suggest that manipulation of intracellular Ca2+ level or CaMKII activity may be exploited for prevention of Cd-induced neurodegenerative disorders.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据