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Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones

Progress in Biophysics and Molecular Biology, ISSN: 0079-6107, Vol: 86, Issue: 2, Page: 279-351
2004
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Review Description

Delayed neuronal death following prolonged (10–15 min) stimulation of Glu receptors is known to depend on sustained elevation of cytosolic Ca 2+ concentration ([Ca 2+ ] i ) which may persist far beyond the termination of Glu exposure. Mitochondrial depolarization (MD) plays a central role in this Ca 2+ deregulation: it inhibits the uniporter-mediated Ca 2+ uptake and reverses ATP synthetase which enhances greatly ATP consumption during Glu exposure. MD-induced inhibition of Ca 2+ uptake in the face of continued Ca 2+ influx through Glu-activated channels leads to a secondary increase of [Ca 2+ ] i which, in its turn, enhances MD and thus [Ca 2+ ] i. Antioxidants fail to suppress this pathological regenerative process which indicates that reactive oxygen species are not involved in its development. In mature nerve cells (>11 DIV), the post-glutamate [Ca 2+ ] i plateau associated with profound MD usually appears after 10–15 min Glu (100 μM) exposure. In contrast, in young cells (<9 DIV) delayed Ca 2+ deregulation (DCD) occurs only after 30–60 min Glu exposure. This difference is apparently determined by a dramatic increase in the susceptibility of mitochondia to Ca 2+ overload during nerve cells maturation. The exact mechanisms of Glu-induced profound MD and its coupling with the impairment of Ca 2+ extrusion following toxic Glu challenge is not clarified yet. Their elucidation demands a study of dynamic changes in local concentrations of ATP, Ca 2+, H +, Na + and protein kinase C using novel methodological approaches.

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