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Oxidative Stress and Neuronal Zinc Signaling

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Zinc Signals in Cellular Functions and Disorders

Abstract

Zinc (Zn2+) is an abundant transition metal that is found in the central nervous system (CNS) at relatively high concentrations. A small fraction of this metal is located within synaptic vesicles in a subpopulation of excitatory neurons along with glutamate, as “chelatable” Zn2+, and can be synaptically released in an activity-dependent fashion. Vesicular Zn2+ can thus act as a neurotransmitter or neuromodulator under physiological conditions. However, under certain pathological conditions excessive synaptically released Zn2+ can translocate into postsynaptic neurons, inducing cell death. There is mounting additional evidence that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critically involved in the pathophysiology of many neuronal diseases, including ischemic stroke. The majority of neuronal Zn2+ exists not within synaptic vesicles, but tightly bound to Zn2+-binding proteins including metallothionein (MT), as well as transcription factors with zinc-finger domains. Under pathological conditions, oxidative and nitrosative stress causes oxidation and S-nitrosylation of cysteine thiols in Zn2+-containing proteins, liberating the bound metal. Oxidative stress-induced elevation of intracellular Zn2+ can activate various deleterious cell-signaling pathways, sometimes with disastrous consequences. As such, Zn2+-containing proteins such as MT serve as redox-sensitive molecular switches for zinc signals, playing a critical role in the regulation of neuronal function and viability.

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Acknowledgments

The authors thank the members of their laboratories who have contributed to zinc-related research during the past several years. This work has been supported by JSPS KAKENHI Grant Number 23590644 (to H.H.) and by US NIH grant NS043277 (to E.A.).

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Authors and Affiliations

  1. Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan

    Hirokazu Hara

  2. Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Elias Aizenman

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  1. Hirokazu Hara
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  2. Elias Aizenman
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Correspondence to Hirokazu Hara .

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  1. Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

    Toshiyuki Fukada

  2. Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Taiho Kambe

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Hara, H., Aizenman, E. (2014). Oxidative Stress and Neuronal Zinc Signaling. In: Fukada, T., Kambe, T. (eds) Zinc Signals in Cellular Functions and Disorders. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55114-0_4

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