Journal
EUROPEAN JOURNAL OF BIOCHEMISTRY
Volume 271, Issue 11, Pages 2060-2066Publisher
WILEY
DOI: 10.1111/j.1432-1033.2004.04132.x
Keywords
Alzheimer's disease; cerebral ischemia; mitogen activated protein kinases; neurodegeneration; neuronal cell death; oxidative stress; Parkinson's disease; phosphatases; reactive oxygen species; traumatic brain injury
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Funding
- NINDS NIH HHS [R01 NS 40817, R01 NS038319, R01 NS 38319, R01 NS040817, F30 NS043824, F30 NS 43824] Funding Source: Medline
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The extracellular signal regulated protein kinases (ERK1/2) are essential for normal development and functional plasticity of the central nervous system. However, a growing number of recent studies in models of cerebral ischemia, brain trauma and neurodegenerative diseases implicate a detrimental role for ERK1/2 signaling during oxidative neuronal injury. Neurons undergoing oxidative stress-related injuries typically display a biphasic or sustained pattern of ERK1/2 activation. A variety of potential targets of reactive oxygen species and reactive nitrogen species could contribute to ERK1/2 activation. These include cell surface receptors, G proteins, upstream kinases, protein phosphatases and proteasome components, each of which could be direct or indirect targets of reactive oxygen or nitrogen species, thereby modulating the duration and magnitude of ERK1/2 activation. Neuronal oxidative stress also appears to influence the subcellular trafficking and/or localization of activated ERK1/2. Differences in compartmentalization of phosphorylated ERK1/2 have been observed in diseased or injured human neurons and in their respective animal and cell culture model systems. We propose that differential accessibility of ERK1/2 to downstream targets, which is dictated by the persistent activation of ERK1/2 within distinct subcellular compartments, underlies the neurotoxic responses that are driven by this kinase.
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