The zinc sensing receptor, a link between zinc and cell signaling

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 phosphatidylinositol 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.

Figure 1

A. The Zn²⁺ –dependent Ca²⁺ rise triggered in HaCaT, keratinocytic cell line, is insensitive to the general tyrosine kinase inhibitor genistein. B. A model for ZnR signaling mediating Zn²⁺ –dependent cell growth and survival. Our results indicate that a ZnR is the major link between changes in extracellular Zn²⁺ and physiological cell function, such as: secretion, proliferation and survival. Desensitization, induced by Zn²⁺, largely attenuates the Zn²⁺ –dependent signaling.

Figure 2

Extracellular Zn²⁺ –signaling, activated by the putative ZnR, reduces butyrate induced cell death. Colonocytic culture, HT29 cells, was treated with butyrate (30 mM, 24 h) and cells were imaged using brightfield microscopy. Massive loss of cells is observed (left picture) following the butyrate treatment. Application of Zn²⁺ for ten minutes prior to the butyrate treatment reduced the loss of cells in the culture (right picture).

Figure 3

Extracellular Zn²⁺ –signaling, activated by the putative ZnR, enhanced cell growth of prostate cancer cells. Prostate cancer cell line, PC–3, was treated with Zn²⁺ –containing (100 μM, ten minutes) or Zn²⁺ –free Ringer’s solution daily, for five days. Cultures were then stained with crystal violet. Enhanced cell growth is shown in the cells treated with Zn²⁺ (right picture) compared with the control cells (left picture).