15032707

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2

Zn(2+) plays an important role in diverse physiological processes, but when released in excess amounts it is potently neurotoxic. In vivo trans-synaptic movement and subsequent post-synaptic accumulation of intracellular Zn(2+) contributes to the neuronal injury observed in some forms of cerebral ischemia. Zn(2+) may enter neurons through NMDA channels, voltage-sensitive calcium channels, Ca(2+)-permeable AMPA/kainate (Ca-A/K) channels, or Zn(2+)-sensitive membrane transporters. Furthermore, Zn(2+) is also released from intracellular sites such as metallothioneins and mitochondria. The mechanisms by which Zn(2+) exerts its potent neurotoxic effects involve many signaling pathways, including mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS) and disruption of metabolic enzyme activity, ultimately leading to activation of apoptotic and/or necrotic processes. As is the case with Ca(2+), neuronal mitochondria take up Zn(2+) as a way of modulating cellular Zn(2+) homeostasis. However, excessive mitochondrial Zn(2+) sequestration leads to a marked dysfunction of these organelles, characterized by prolonged ROS generation. Intriguingly, in direct comparison to Ca(2+), Zn(2+) appears to induce these changes with a considerably greater degree of potency. These effects are particularly evident upon large (i.e., micromolar) rises in intracellular Zn(2+) concentration ([Zn(2+)](i)), and likely hasten necrotic neuronal death. In contrast, sub-micromolar [Zn(2+)](i) increases promote release of pro-apoptotic factors, suggesting that different intensities of [Zn(2+)](i) load may activate distinct pathways of injury. Finally, Zn(2+) homeostasis seems particularly sensitive to the environmental changes observed in ischemia, such as acidosis and oxidative stress, indicating that alterations in [Zn(2+)](i) may play a very significant role in the development of ischemic neuronal damage.

eng

IM

MEDLINE

1566-5240

Print

NLM

87-111

pubmed-meshheading:15032707-Animals, pubmed-meshheading:15032707-Apoptosis, pubmed-meshheading:15032707-Biological Transport, pubmed-meshheading:15032707-Brain, pubmed-meshheading:15032707-Calcium, pubmed-meshheading:15032707-Cytosol, pubmed-meshheading:15032707-Hippocampus, pubmed-meshheading:15032707-Homeostasis, pubmed-meshheading:15032707-Humans, pubmed-meshheading:15032707-Ions, pubmed-meshheading:15032707-Ischemia, pubmed-meshheading:15032707-Mice, pubmed-meshheading:15032707-Microscopy, Confocal, pubmed-meshheading:15032707-Mitochondria, pubmed-meshheading:15032707-Models, Biological, pubmed-meshheading:15032707-N-Methylaspartate, pubmed-meshheading:15032707-Neurons, pubmed-meshheading:15032707-Protein Transport, pubmed-meshheading:15032707-Reactive Oxygen Species, pubmed-meshheading:15032707-Synapses, pubmed-meshheading:15032707-Time Factors, pubmed-meshheading:15032707-Zinc

Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury.

Journal Article, Research Support, U.S. Gov't, P.H.S., Review, Research Support, Non-U.S. Gov't