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CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death
Author(s) -
Chen Sujuan,
Xu Yijiao,
Xu Baoshan,
Guo Min,
Zhang Zhen,
Liu Lei,
Ma Hongwei,
Chen Zi,
Luo Yan,
Huang Shile,
Chen Long
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07493.x
Subject(s) - mapk/erk pathway , pi3k/akt/mtor pathway , kinase , programmed cell death , microbiology and biotechnology , chemistry , intracellular , protein kinase a , p38 mitogen activated protein kinases , phosphorylation , calcium in biology , signal transduction , apoptosis , biology , biochemistry
J. Neurochem. (2011) 119 , 1108–1118. Abstract Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently, we have shown that Cd elevates intracellular free calcium ion ([Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ with 1,2‐bis( o ‐aminophenoxy) ethane‐ N , N , N ′, N ′‐tetraacetic acid tetra(acetoxymethyl) ester or preventing Cd‐induced [Ca 2+ ] 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 [Ca 2+ ] 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 Ca 2+ level or CaMKII activity may be exploited for prevention of Cd‐induced neurodegenerative disorders.