Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury
Autor: | Jeng Jm, Sensi Sl |
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Rok vydání: | 2004 |
Předmět: |
N-Methylaspartate
Time Factors Kainate receptor Apoptosis AMPA receptor Mitochondrion medicine.disease_cause Biochemistry Hippocampus Models Biological Mice Cytosol Ischemia medicine Animals Homeostasis Humans Molecular Biology chemistry.chemical_classification Ions Neurons Reactive oxygen species Microscopy Confocal Voltage-dependent calcium channel Chemistry Brain Biological Transport General Medicine Cell biology Mitochondria Protein Transport Zinc Anesthesia Synapses Molecular Medicine Calcium Reactive Oxygen Species Intracellular Oxidative stress |
Zdroj: | Current molecular medicine. 4(2) |
ISSN: | 1566-5240 |
Popis: | 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. |
Databáze: | OpenAIRE |
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