title: CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death.
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.
authors.affiliation: College of Life Sciences, Nanjing Normal University, Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Nanjing, China.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Yijiao
authors.initials: Y
authors.lastname: Xu
authors.forename: Baoshan
authors.initials: B
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.forename: Zi
authors.initials: Z
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002104:Cadmium / Q000502:physiology* / Q000633:toxicity; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D002104:Cadmium; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2