Disrupted [Ca2+]i Homeostasis Contributes to the Toxicity of Nitric Oxide in Cultured Hippocampal Neurons (original) (raw)

2002, Journal of Neurochemistry

Nitric oxide (NO) has been shown to be an important mediator in several forms of neurotoxicity. We previously reported that NO alters intracellular Ca2concentration ([Ca2~],)homeostasis in cultured hippocampal neurons during 20-mm exposures. In this study, we examine the relationship between late alterations of [Ca2~] homeostasis and the delayed toxicity produced by NO. The NO-releasing agent S-nitrosocysteine (SNOC; 300 iiM) reduced survival by about one half 1 day after 20mm exposures, as did other NO-releasing agents. SNOC also was found to produce prolonged elevations of [Ca2] 1,persisting at 2 and 6 h. Hemoglobin, a scavenger of NO, blocked both the late [Ca 2~] elevation and the delayed toxicity of SNOC. Removal of extracellular Ca2d uring the 20-mm SNOC treatment failed to prevent the late [Ca2~] elevations and did not prevent the delayed toxicity, but removal of extracellular Ca2~for the 6 h after exposure as well blocked most of the toxicity. Western blots showed that SNOC exposure resulted in an increased proteolytic breakdown of the structural protein spectrin, generating a fragment with immunoreactivity suggesting activity of the Ca2~-activatedprotease calpain. The spectrin breakdown and the toxicity of SNOC were inhibited by treatment with calpain antagonists. We conclude that exposures to toxic levels of NO cause prolonged disruption of [Ca2~],homeostatic mechanisms, and that the resulting persistent [Ca2~] elevations contribute to the delayed neurotoxicity of NO.

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