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ToxSci Advance Access originally published online on May 3, 2006
Toxicological Sciences 2006 92(2):464-475; doi:10.1093/toxsci/kfl006
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Copper-Induced Stimulation of Extracellular Signal-Regulated Kinase in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+, and Cell Energetics and the Impact of Extracellular Signal-Regulated Kinase Signaling on Apoptosis and Necrosis

Muhammad Nawaz*,{dagger}, Claudia Manzl{ddagger}, Veronika Lacher* and Gerhard Krumschnabel*,{dagger},1

* Institut für Zoologie und Limnologie and {dagger} Center of Molecular Biosciences, Leopold Franzens Universität Innsbruck, A-6020 Innsbruck, Austria; and {ddagger} Laboratory of Comparative Immunology, Division of Experimental Pathophysiology and Immunology, Innsbruck Medical University, A-6020 Innsbruck, Austria

Received March 14, 2006; accepted April 27, 2006

The present study investigated if copper (Cu) exposure of trout hepatocytes, which stimulates formation of reactive oxygen species (ROS) and increases intracellular free Ca2+ (Ca2+i), leads to an activation of extracellular signal-regulated kinase (ERK), the mechanisms underlying this activation, and the role of ERK signaling in cell death. Cu stimulated a time- and dose-dependent increase of phosphorylated extracellular signal-regulated kinase (pERK), and preventing the associated Ca2+ influx or radical formation diminished or inhibited ERK activation, respectively. Furthermore, Cu enhanced caspase 3/7 activity and necrosis, and both effects were inhibited by treatments diminishing radical production and by chelating extracellular Ca2+. In addition, ERK activity, and to a lesser extent caspase activity, was reduced by inhibiting mitochondrial ATP production, suggesting ATP dependence of the process. Inhibition of the ERK activator MEK, as well as of p38, significantly reduced caspase activation and necrosis, whereas c-Jun N-terminal kinase (JNK) inhibition diminished only caspase activity. Likewise, inhibition of MEK and p38, but not of JNK, prevented Cu-induced ROS production. In summary, we found that stimulation of ERK by Cu exposure of trout hepatocytes is dependent on radical formation and ATP, whereas Ca2+ only modulates ERK activity. At the same time, activated ERK, as well as p38, contributes to enhanced ROS formation, whereas JNK did not. All three mitogen-activated protein kinases appear to promote apoptotic cell death upon Cu exposure, and ERK and p38 also stimulate necrosis.

Key Words: copper toxicity; extracellular signal-regulated kinase; Ca2+; reactive oxygen species; p38; c-Jun N-terminal kinase; apoptosis; necrosis.


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H. L. Ebner, M. Blatzer, M. Nawaz, and G. Krumschnabel
Activation and nuclear translocation of ERK in response to ligand-dependent and -independent stimuli in liver and gill cells from rainbow trout
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