The extracellular zinc-sensing receptor mediates intercellular communication by inducing ATP release

Haleli Sharir, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Taste and salivary secretion disorders have been linked to zinc deficiency, indeed zinc is found in secretory granules in the salivary gland. The signaling role for the zinc release in this tissue, however, is poorly understood. Here, we address the signaling pathways and physiological role of the zinc-sensing receptor, ZnR, in the ductal salivary gland cell line, HSY. Exposure of these cells to zinc triggered intracellular Ca2+ release from thapsigargin-sensitive stores. The Gαq inhibitor, YM-254890 (1 μM), eliminated the Zn2+-dependent Ca2+ response, demonstrating that ZnR is a Gαq-coupled receptor. Dose-response curves yielded an apparent K0.5 of 36 μM and a Hill coefficient of 7 in the absence of extracellular Ca2+, and K0.5 of 55 μM with a Hill coefficient of 3 in its presence. This indicates that although Zn2+ is essential for ZnR activation, Ca2+ may affect the receptor co-operativity. The homologous desensitization pattern of ZnR was characterized by pre-exposure of cells to Zn2+ at concentrations found to activate the receptor. Re-exposure of cells to Zn2+ elicited an attenuated Zn2+-dependent Ca2+ response for at least 3 h, indicating that the ZnR is strongly desensitized by Zn2+. Finally, we studied the paracrine affects of ZnR using a co-culture consisting of the HSY cells and vascular smooth muscle cells (VSMCs). While no Zn2+-dependent Ca 2+ release was observed in VSMC alone, application of Zn2+ to the co-culture induced a Ca2+ rise in both HSY cells and VSMC. This Ca2+ rise was inhibited by the ATP scavenger, apyrase. Taken together, our results demonstrate that ZnR activity is monitored in salivary cells and is modulated by extracellular Ca2+. We further show that ZnR enhances secretion of ATP, thereby linking zinc to key signaling pathways involved in modification of salivary secretions by the ductal cells.

Original languageEnglish
Pages (from-to)845-852
Number of pages8
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - 8 Jul 2005


  • Desensitization
  • Extracellular cation-sensing receptor
  • GPCR
  • Zinc-sensing receptor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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