CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death

Abstract

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 ([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.