Nitric Oxide Disrupts Ca2+ Homeostasis in Hippocampal Neurons |
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Authors: | James R Brorson Reginaldo A Sulit He Zhang |
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Institution: | Department of Neurology and the Committees on Neurobiology and Cell Physiology, and; Section of Neurosurgery, Department of Surgery, University of Chicago, Chicago, Illinois, U.S.A. |
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Abstract: | Abstract: Nitric oxide has been recognized in recent years as an important mediator of neuronal toxicity, which in many cases involves alterations of the cytoplasmic Ca2+ concentration (Ca2+]i). In Ca2+]i fluorimetric experiments on cultured hippocampal neurons, the nitric oxide-releasing agent S -nitrosocysteine produced a delayed rise in Ca2+]i over a 20-min exposure, which was accompanied by a progressive slowing of the kinetics of recovery from depolarization-induced Ca2+]i transients. These effects were blocked by oxyhemoglobin and by superoxide dismutase, confirming nitric oxide as the responsible agent, and suggesting that they involved peroxynitrite formation. Similar alterations of Ca2+]i homeostasis were produced by the mitochondrial ATP synthase inhibitor oligomycin, and when an ATP-regenerating system was supplied via the patch pipette in combined whole-cell patch-clamp-Ca2+]i fluorimetry experiments, S -nitrosocysteine had no effect on the resting Ca2+]i or on the recovery kinetics of Ca2+]i transients induced by direct depolarization. We conclude that prolonged exposure to nitric oxide disrupts Ca2+]i homeostasis in hippocampal neurons by impairing Ca2+ removal from the cytoplasm, possibly as a result of ATP depletion. The resulting persistent alterations in Ca2+]i may contribute to the delayed neurotoxicity of nitric oxide. |
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Keywords: | Nitric oxide Calcium Hippocampus Excitotoxicity Peroxynitrite Mitochondria |
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