Glutamate mobilizes [Zn2+] through Ca2+ -dependent reactive oxygen species accumulation |
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Authors: | Dineley Kirk E Devinney Michael J Zeak Jennifer A Rintoul Gordon L Reynolds Ian J |
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Institution: | Department of Biology, Francis Marion University, Florence, SC, USA; Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada |
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Abstract: | Liberation of zinc from intracellular stores contributes to oxidant-induced neuronal injury. However, little is known regarding how endogenous oxidant systems regulate intracellular free zinc (Zn(2+)](i)). Here we simultaneously imaged Ca(2+)](i) and Zn(2+)](i) to study acute Zn(2+)](i) changes in cultured rat forebrain neurons after glutamate receptor activation. Neurons were loaded with fura-2FF and FluoZin-3 to follow Ca(2+)](i) and Zn(2+)](i), respectively. Neurons treated with glutamate (100 microM) for 10 min gave large Ca(2+) responses that did not recover after termination of the glutamate stimulus. Glutamate also increased Zn(2+)](i), however glutamate-induced Zn(2+)](i) changes were completely dependent on Ca(2+) entry, appeared to arise entirely from internal stores, and were substantially reduced by co-application of the membrane-permeant chelator TPEN during the glutamate treatment. Pharmacological maneuvers revealed that a number of endogenous oxidant producing systems, including nitric oxide synthase, phospholipase A(2), and mitochondria all contributed to glutamate-induced Zn(2+)](i) changes. We found no evidence that mitochondria buffered Zn(2+)](i) during acute glutamate receptor activation. We conclude that glutamate-induced Zn(2+)](i) transients are caused in part by Ca(2+)](i)-induced reactive oxygen species that arises from both cytosolic and mitochondrial sources. |
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Keywords: | excitotoxicity FluoZin-3 intracellular calcium intracellular zinc mitochondria reactive oxygen species |
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