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Molecular Medicine

, Volume 13, Issue 7–8, pp 331–336 | Cite as

The Zinc Sensing Receptor, a Link Between Zinc and Cell Signaling

  • Michal Hershfinkel
  • William F. Silverman
  • Israel Sekler
Proceedings

Abstract

Zinc is essential for cell growth. For many years it has been used to treat various epithelial disorders, ranging from wound healing to diarrhea and ulcerative colon disease. The physiological/molecular mechanisms linking zinc and cell growth, however, are not well understood. In recent years, Zn2+ has emerged as an important signaling molecule, activating intracellular pathways and regulating cell fate. We have functionally identified an extracellular zinc sensing receptor, called zinc sensing receptor (ZnR), that is specifically activated by extracellular Zn2+ at physiological concentrations. The putative ZnR is pharmacologically coupled to a Gq-protein which triggers release of Ca2+ from intracellular stores via the Inositol 1,4,5-trisphosphate (IP3) pathway. This, in turn results in downstream signaling via the MAP and phosphatydilinositol 3-kinase (PI3 kinase) pathways that are linked to cell proliferation. In some cell types, e.g., colonocytes, ZnR activity also upregulates Na+/H+ exchange, mediated by Na+/H+ exchanger isoform 1 (NHE1), which is involved in cellular ion homeostasis in addition to cell proliferation. Our overall hypothesis, as discussed below, is that a ZnR, found in organs where dynamic zinc homeostasis is observed, enables extracellular Zn2+ to trigger intracellular signaling pathways regulating key cell functions. These include cell proliferation and survival, vectorial ion transport and hormone secretion. Finally, we suggest that ZnR activity found in colonocytes is well positioned to attenuate erosion of the epithelial lining of the colon, thereby preventing or ameliorating diarrhea, but, by signaling through the same pathways, a ZnR may enhance tumor progression in neoplastic disease.

Notes

Acknowledgments

This work was supported in part by Binational Science Foundation grants 2001101 and 2003201 and by the Israel Science Foundation grant 585/05 (to M. H.). We would like to thank Ms. Noga Dubi, Ms. Anna Buruchin and Ms. Hagit Azriel-Tamir for technical assistance.

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Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Michal Hershfinkel
    • 1
  • William F. Silverman
    • 1
  • Israel Sekler
    • 2
  1. 1.Department of Morphology, Faculty of Health Science, The Zlotowski Center for NeuroscienceBen Gurion University of the NegevBeer-ShevaIsrael
  2. 2.Department of Physiology, Faculty of Health Science, The Zlotowski Center for NeuroscienceBen Gurion University of the NegevBeer-ShevaIsrael

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