title: Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury.
abstract: 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.
authors.affiliation: Department of Neurology, University of California, Irvine. Irvine, CA 92697-4292, USA. ssensi@uci.edu
authors.forename: S L
authors.initials: SL
authors.lastname: Sensi
authors.forename: J-M
authors.initials: JM
authors.lastname: Jeng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007477:Ions / Q000378:metabolism; D007511:Ischemia; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D017382:Reactive Oxygen Species; D013569:Synapses / Q000502:physiology*; D013997:Time Factors; D015032:Zinc / Q000378:metabolism / Q000502:physiology*
chemical_list: D007477:Ions; D017382:Reactive Oxygen Species; D016202:N-Methylaspartate; D015032:Zinc; D002118:Calcium