Zinc Released from Injured Cells Is Acting via the Zn2+-sensing Receptor, ZnR, to Trigger Signaling Leading to Epithelial Repair

• Published in: The Journal of biological chemistry Vol. 285; no. 34; pp. 26097 - 26106
• Main Authors: Sharir, Haleli, Zinger, Anna, Nevo, Andrey, Sekler, Israel, Hershfinkel, Michal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2010; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphate; Calcium Imaging; Calcium Intracellular Release; Calcium Signaling; Cell Biology; Cell Line; Cell pH; Epithelial Cell; Epithelial Cells; Humans; Keratinocytes - pathology; Keratinocytes - physiology; Membrane Biology; Molecular Probes; Na/H Exchanger; Pyridines; Receptors, G-Protein-Coupled - physiology; Wound Healing; Zinc; Zinc - metabolism; Zinc Homeostasis; Zinc Transport; Calcium Imaging; Zinc Transport; Cell pH; Epithelial Cell; Zinc Homeostasis; Na/H Exchanger; Calcium Intracellular Release; Zinc
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.107490

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.