Sci. STKE, 10 February 2004
NEUROBIOLOGY NO and Zinc Crosstalk to Death
Excessive nitric oxide and the release of zinc from intracellular stores have been linked to neuronal death associated with stroke and some neurodegenerative diseases, but the mechanisms that mediate their neurotoxic effects have not been clear. Bossy-Wetzel et al. have determined that zinc is an important component of the NO-neurotoxicity pathway. An increase in intracellular zinc and its localization to mitochondria was observed in cultured cerebrocortical neurons exposed to NO insult. Pretreatment of neurons with a free radical scavenger blocked this effect, indicating that reaction of NO with reactive oxygen species (ROS) to form neurotoxic peroxynitrate is required. Zinc blocked respiration in isolated mitochondria, which suggested that this organelle is a key target of zinc-mediated toxicity. The presence of a zinc chelator blocked NO-induced activation of p38 mitogen-activated protein kinase (MAPK), a critical signaling molecule in the NO-response pathway. NO exposure was also associated with potassium efflux and cell shrinkage, a morphological change characteristic of neuronal apoptosis. Treatment of neurons with a potassium channel antagonist, a zinc chelator, a ROS scavenger, or an inhibitor of p38 MAPK decreased NO-mediated neuronal cell death. The authors propose a signaling pathway in which NO triggers zinc-mediated inhibition of mitochondrial function. This could underlie an increase in ROS production and subsequent ROS reaction with NO to activate p38 MAPK, which could then directly or indirectly alter potassium channel function and lead to progressive cell death. The authors propose a signaling pathway in which NO triggers zinc-mediated inhibition of mitochondrial function. [For a discussion of zinc signaling, please see the STKE Forum.]
E. Bossy-Wetzel, M. V. Talantova, W. D. Lee, M. N. Schölzke, A. Harrop, E. Mathews, T. Götz, J. Han, A. Harrop, M. H. Ellisman, G. A. Perkins, S. A. Lipton, Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 41, 351-365 (2004). [Online Journal]
Citation: NO and Zinc Crosstalk to Death. Sci. STKE 2004, tw50 (2004).
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