Zinc released from injured cells is acting via the Zn²⁺-sensing receptor, ZnR, to trigger signaling leading to epithelial repair

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 Zn ²⁺ 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, Zn ²⁺ 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.