期刊
NEURON
卷 41, 期 3, 页码 351-365出版社
CELL PRESS
DOI: 10.1016/S0896-6273(04)00015-7
关键词
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资金
- NCRR NIH HHS [P41 RR04050] Funding Source: Medline
- NEI NIH HHS [R01 EY05477, R01 EY09024] Funding Source: Medline
- NICHD NIH HHS [P01 HD29587] Funding Source: Medline
- NINDS NIH HHS [R01 NS44314, R01 NS41207, R01 NS14718, R01 NS047456] Funding Source: Medline
Nitric oxide (NO) and zinc (Zn2+) are implicated in the pathogenesis of cerebral ischemia and neurodegenerative diseases. However, their relationship and the molecular mechanism of their neurotoxic effects remain unclear. Here we show that addition of exogenous NO or NMDA (to increase endogenous NO) leads to peroxynitrite (ONOO-) formation and consequent Zn2+ release from intracellular stores in cerebrocortical neurons. Free Zn2+ in turn induces respiratory block, mitochondrial permeability transition (mPT), cytochrome c release, generation of reactive oxygen species (ROS), and p38 MAP kinase activation. This pathway leads to caspase-independent K+ efflux with cell volume loss and apoptotic-like death. Moreover, Zn2+ chelators, ROS scavengers, Bcl-x(L), dominant-interfering p38, or K+ channel blockers all attenuate NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these data establish a new form of crosstalk between NO and Zn2+ apoptotic signal transduction pathways that may contribute to neurodegeneration.
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