- Capacitative calcium influx plays an important role in shaping the Ca2+ response of various tissues and cell types. Inhibition by heavy metals is a hallmark of store-operated calcium channel (SOCC) activity. Paradoxically, although zinc is the only potentially physiological relevant ion, it is the least investigated in terms of inhibitory mechanism. In the present study, we characterize the inhibitory mechanism of the SOCC by Zn2+ in the human salivary cell line, HSY, and rat salivary submandibular ducts and acini by monitoring SOCC activity using fluorescence imaging. Analysis of Zn2+ inhibition indicated that Zn2+ acts as a competitive inhibitor of Ca2+ influx but does not permeate through the SOCC, suggesting that Zn2+ interacts with an extracellular site of SOCC. Application of the reducing agents, dithiothreitol (DTT) and β-mercaptoethanol, totally eliminated Zn2+ and Cd2+ inhibition of SOCC, suggesting that cysteines are part of the Zn2+ and Cd2+ binding site. Interestingly, reducing conditions failed to eliminate the inhibition of SOCC by La3+ and Gd3+, indicating that the Zn2+ and lanthanides binding sites are distinct. Finally, we show that changes in redox potential and Zn2+ are regulating, via SOCC activity, the agonist-induced Ca2+ response in salivary ducts. The presence of a specific Zn2+ site, responsive to physiological Zn2+ and redox potential, may not only be instrumental for future structural studies of various SOCC candidates but may also reveal novel physiological aspects of the interaction between zinc, redox potential, and cellular Ca2+ homeostasis.