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Publication Detail
Excitotoxic mitochondrial depolarisation requires both calcium and nitric oxide in rat hippocampal neurons.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Keelan J, Vergun O, Duchen MR
  • Publication date:
  • Pagination:
    797, 813
  • Journal:
    J Physiol
  • Volume:
    520 Pt 3
  • Status:
  • Country:
  • Print ISSN:
  • PII:
  • Language:
  • Keywords:
    Animals, Calcium, Culture Techniques, Cytosol, Electrophysiology, Fluorescent Dyes, Fura-2, Glutamic Acid, Hippocampus, Mitochondria, Neurons, Nitric Oxide, Osmolar Concentration, Rats, Rhodamine 123
1. Glutamate neurotoxicity has been attributed to cellular Ca2+ overload. As mitochondrial depolarisation may represent a pivotal step in the progression to cell death, we have used digital imaging techniques to examine the relationship between cytosolic Ca2+ concentration ([Ca2+]c) and mitochondrial potential (DeltaPsim) during glutamate toxicity, and to define the mechanisms underlying mitochondrial dysfunction. 2. In cells of > 11 days in vitro (DIV), exposure to 50 mM potassium or 100 microM glutamate had different consequences for DeltaPsim. KCl caused a small transient loss of DeltaPsim but in response to glutamate there was a profound loss of DeltaPsim. In cells of 7-10 DIV, glutamate caused only a modest and reversible drop in DeltaPsim. 3. Using fura-2 to measure [Ca2+]c, responses to KCl and glutamate did not appear significantly different. However, use of the low affinity indicator fura-2FF revealed a difference in the [Ca2+]c responses to KCl and glutamate, which clearly correlated with the loss of DeltaPsim. Neurons exhibiting a profound mitochondrial depolarisation also showed a large secondary increase in the fura-2FF ratio. 4. The glutamate-induced loss of DeltaPsim was dependent on Ca2+ influx. However, inhibition of nitric oxide synthase (NOS) by L-NAME significantly attenuated the loss of DeltaPsim. Furthermore, photolysis of caged NO at levels that had no effect alone promoted a profound mitochondrial depolarisation when combined with high [Ca2+]c, either in response to KCl or to glutamate in cultures at 7-10 DIV. 5. In cells that showed only modest mitochondrial responses to glutamate, induction of a mitochondrial depolarisation by the addition of NO was followed by a secondary rise in [Ca2+]c. These data suggest that [Ca2+]c and nitric oxide act synergistically to cause mitochondrial dysfunction and impaired [Ca2+]c homeostasis during glutamate toxicity.
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