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  • Title: Peroxynitrite modulates the activation of p38 and extracellular regulated kinases in PC12 cells.
    Author: Jope RS, Zhang L, Song L.
    Journal: Arch Biochem Biophys; 2000 Apr 15; 376(2):365-70. PubMed ID: 10775424.
    Abstract:
    Although peroxynitrite appears to contribute to neuronal dysfunction in several neurodegenerative disorders, little is known about how peroxynitrite affects cellular signaling processes. This study investigated if peroxynitrite affects the mitogen-activated protein kinases, extracellular-regulated kinases 1 and 2 (ERK1/2) and p38. Exposure of PC12 cells to 500 microM peroxynitrite activated ERK1/2 and p38 within 5 min and this was followed by gradual decreases in activation over the next 25 min. Activation of ERK1/2 by peroxynitrite was mediated by activation of the epidermal growth factor (EGF) receptor in a calcium/calmodulin-dependent kinase II- and src family tyrosine kinase-dependent manner, as it was blocked by the selective EGF receptor inhibitor AG1478, by KN62, an inhibitor of calcium/calmodulin-dependent kinase II, and by PP1, a src family tyrosine kinase inhibitor. Activation of p38 by peroxynitrite was independent of the EGF receptor, required activation of calcium/calmodulin-dependent kinase II and src family tyrosine kinases, and was modulated by nerve growth factor (NGF) in a time-dependent manner. Pretreatment with NGF (2 h) attenuated, whereas cotreatment with NGF potentiated, peroxynitrite-induced activation of p38. Thus, peroxynitrite activates ERK1/2 and p38, activation of EGF receptors, calcium/calmodulin-dependent kinase II, and src family tyrosine kinases participate in these signaling responses to peroxynitrite, and peroxynitrite- and NGF-induced signaling activities converge on p38.
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