Zinc Released from Injured Cells Is Acting via the Zn2+-sensing Receptor,ZnR, to Trigger Signaling Leading to Epithelial Repair |
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Authors: | Haleli Sharir Anna Zinger Andrey Nevo Israel Sekler Michal Hershfinkel |
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Affiliation: | From the Departments of ‡Morphology and ;§Physiology, Faculty of Health Sciences, Ben Gurion University, Beer-Sheva 84105, Israel |
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Abstract: | A role for Zn2+ in accelerating wound healing is established, yet, the signaling pathways linking Zn2+ to tissue repair are not well known. We show that in the human HaCaT keratinocytes extracellular Zn2+ induces a metabotropic Ca2+ response that is abolished by silencing the expression of the G-protein-coupled receptor GPR39, suggesting that this Zn2+-sensing receptor, ZnR, is mediating the response. Keratinocytic-ZnR signaling is highly selective for Zn2+ and can be triggered by nanomolar concentrations of this ion. Interestingly, Zn2+ was also released following cellular injury, as monitored by a specific non-permeable fluorescent Zn2+ probe, ZnAF-2. Chelation of Zn2+ and scavenging of ATP from conditioned medium, collected from injured epithelial cultures, was sufficient to eliminate the metabotropic Ca2+ signaling. The signaling triggered by Zn2+, via ZnR, or by ATP further activated MAP kinase and induced up-regulation of the sodium/proton exchanger NHE1 activity. Finally, activation of ZnR/GPR39 signaling or application of ATP enhanced keratinocytes scratch closure in an in vitro model. Thus our results indicate that extracellular Zn2+, which is either applied or released following injury, activates ZnR/GPR39 to promote signaling leading to epithelial repair. |
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Keywords: | Calcium Imaging Calcium Intracellular Release Cell pH Epithelial Cell Zinc Na/H Exchanger Zinc Homeostasis Zinc Transport |
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