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ToxSci Advance Access first published online on May 3, 2006
This version published online on May 16, 2006
Toxicological Sciences, 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
Received March 14, 2006
Accepted April 27, 2006

In Vitro Toxicology

Copper-Induced Stimulation of ERK in Trout Hepatocytes: The Role of Reactive Oxygen Species, Ca2+ and Cell Energetics and the Impact of ERK Signalling on Apoptosis and Necrosis

Muhammad Nawaz 1, Claudia Manzl 2, Veronika Lacher 3, and Gerhard Krumschnabel 1 *

1 Institut für Zoologie und Limnologie, Technikerstraße 25, A-6020 Innsbruck, Austria; Center of Molecular Biosciences, Leopold Franzens Universität Innsbruck, Technikerstraße 25, A-6020 Innsbruck, Austria
2 Laboratory of Comparative Immunology, Division of Experimental Pathophysiology and Immunology, Innsbruck Medical University, Schoepfstraße 41, A-6020 Innsbruck, Austria
3 Institut für Zoologie und Limnologie, Technikerstraße 25, A-6020 Innsbruck, Austria

* To whom correspondence should be addressed.
Gerhard Krumschnabel, E-mail: Gerhard.Krumschnabel{at}uibk.ac.at


  Abstract

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 ERK, the mechanisms underlying this activation, and the role of ERK signalling in cell death. Cu stimulated a time- and dose-dependent increase of phosphorylated ERK (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, were 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 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, contribute to enhanced ROS formation, whereas JNK did not. All three MAP-kinases appear to promote apoptotic cell death upon Cu-exposure, and ERK and p38 also stimulate necrosis.

Keywords: Copper toxicity; extracellular signal-regulated kinase; Ca2+, reactive oxygen species; p38; c-Jun N-terminal kinase; apoptosis, necrosis.
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[Abstract] [Full Text] [PDF]


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