A zinc-sensing receptor triggers the release of intracellular Ca²⁺ and regulates ion transport

Changes in extracellular zinc concentration participate in modulating fundamental cellular processes such as proliferation, secretion, and ion transport in a mechanism that is not well understood. Here, we show that a micromolar concentration of extracellular zinc triggers a massive release of calcium from thapsigargin-sensitive intracellular pools in the colonocytic cell line HT29. Calcium release was blocked by a phospholipase-C inhibitor, indicating that formation of inositol 1,4,5-triphosphate is required for zinc-dependent calcium release. Zinc influx was not observed, indicating that extracellular zinc triggered the release. The Ca_i²⁺ release was zinc specific and could not be triggered by other heavy metals. Furthermore, zinc failed to activate the Ca²⁺-sensing receptor heterologously expressed in HEK293 cells. The zinc-induced Ca_i²⁺ rise stimulated the activity of the Na⁺/H⁺ exchanger in HT29 cells. Our results indicate that a previously uncharacterized extracellular, G protein-coupled, Zn²⁺-sensing receptor is functional in colonocytes. Because Ca_i²⁺ rise is known to regulate key cellular and signal-transduction processes, the zinc-sensing receptor may provide the missing link between extracellular zinc concentration changes and the regulation of cellular processes.