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The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

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Zinc Signals in Cellular Functions and Disorders

Abstract

The structural role of Zn2+ in stabilizing numerous enzymes and zinc fingers of transcription factors has been well established for several decades. Therefore, the major effects of this metal ion on growth, development, and cognitive function were not surprising. The importance of cellular homeostasis of Zn2+ is underlined by the identification of more than 20 proteins involved in transport of Zn2+ into the cytoplasm and various organelles. In the past decade, evidence for a signaling role of Zn2+ is emerging, suggesting this ion acts as a first and second messenger. Thus, transient changes in extracellular and intracellular Zn2+ were monitored and Zn2+-dependent regulation of multiple signaling pathways was shown. We have identified the function of ZnR, a Gq protein-coupled receptor that triggers the release of Ca2+ via the IP3 pathway. This ZnR-dependent signaling regulates cellular pathways involved in survival and proliferation, such as the MAP and PI3 kinase pathways, as well as modulation of ion transport systems such as the Na+/H+ exchanger or the K+/Cl− co-transporter. The GPR39 was then shown to mediate extracellular Zn2+-dependent ZnR signaling. Here we discuss the major role of ZnR/GPR39 as the link between extracellular Zn2+ and intracellular signaling pathways regulating the physiological function of epithelial and neuronal cells. A major future challenge will be to identify the role of ZnR/GPR39 in diseases linked to Zn2+ dyshomeostasis.

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  1. Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410510, Israel

    Michal Hershfinkel

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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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Hershfinkel, M. (2014). The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance. 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_6

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