Zinc released from injured cells is acting via the Zn2+-sensing receptor, ZnR, to trigger signaling leading to epithelial repair.
A role for Zn(2+) in accelerating wound healing is established, yet, the signaling pathways linking Zn(2+) to tissue repair are not well known. We show that in the human HaCaT keratinocytes extracellular Zn(2+) induces a metabotropic Ca(2+) response that is abolished by silencing the expression of the G-protein-coupled receptor GPR39, suggesting that this Zn(2+)-sensing receptor, ZnR, is mediating the response. Keratinocytic-ZnR signaling is highly selective for Zn(2+) 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 Zn(2+) probe, ZnAF-2. Chelation of Zn(2+) and scavenging of ATP from conditioned medium, collected from injured epithelial cultures, was sufficient to eliminate the metabotropic Ca(2+) signaling. The signaling triggered by Zn(2+), 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 Zn(2+), which is either applied or released following injury, activates ZnR/GPR39 to promote signaling leading to epithelial repair.
Departments of Morphology, Ben Gurion University, Beer-Sheva 84105, Israel.
Haleli
H
Sharir
Anna
A
Zinger
Andrey
A
Nevo
Israel
I
Sekler
Michal
M
Hershfinkel
D000255:Adenosine Triphosphate; D020013:Calcium Signaling; D002460:Cell Line; D004847:Epithelial Cells; D006801:Humans; D015603:Keratinocytes / Q000473:pathology* / Q000502:physiology; D015335:Molecular Probes; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D014945:Wound Healing; D015032:Zinc / Q000378:metabolism*
C495797:GPR39 protein, human; D015335:Molecular Probes; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C462061:ZnAF-2; D000255:Adenosine Triphosphate; D015032:Zinc