Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 05/2006; 281(14):9460-70. DOI: 10.1074/jbc.M510650200
Source: PubMed

ABSTRACT Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species.

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Available from: Jianrong Li, Jul 27, 2015
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    • "We previously reported that glutamate receptor overactivation in oligodendrocytes induces rapid activation of ERK1/2 signaling and increased Dusp6 phosphatase expression, and that levels of phosphorylated ERK1 and 2 (pERK1/2)—which are controlled by Dusp6 phosphatase levels—are pivotal in determining cell death or survival (Domercq et al., 2011). ERK activation could be induced by a cytosolic Zn 21 increase (Zhang et al., 2006) since AMPA/kainate receptors are also permeable to Zn 21 (Sensi et al., 2009). ERK1/2 activation acts as a pro-survival signal in oligodendrocytes through its actions at different steps of the mitochondrial apoptotic pathway and by controlling AMPA receptor permeability (Domercq et al., 2011). "
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    Glia 03/2013; 61(3). DOI:10.1002/glia.22441 · 6.03 Impact Factor
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    • "(Zhang et al., 2006 "
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    • "Therefore, the inhibitory action of nitric oxide on 12-LOX may be, at least partially, due to its attenuation of ERK phosphorylation. We have previously shown that peroxynitrite toxicity to mature OLs is mediated by intracellular zinc release (Zhang et al., 2006). Although the exact sources of labile zinc is unclear, metallothioneins, the low molecular weight and cysteine-rich metal binding proteins, may be one of the major sources from which zinc is released typically in response to thiol oxidization (Maret, 2000). "
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