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

Changes in extracellular zinc concentration participate in modulating funda mental cellular processes such as proliferation, secretion, and ion transpo rt in a mechanism that is not well understood. Here, we show that a micromo lar concentration of extracellular zinc triggers a massive release of calci um from thapsigargin-sensitive intracellular pools in the colonocytic cell line HT29. Calcium release was blocked by a phospholipase-C inhibitor, indi cating that formation of inositol 1,4,5-triphosphate is required for zinc-d ependent calcium release. Zinc influx was not observed, indicating that ext racellular zinc triggered the release. The Ca-i(2+) release was zinc specif ic and could not be triggered by other heavy metals. Furthermore, zinc fail ed to activate the Ca2+-sensing receptor heterologously expressed in HEK293 cells. The zinc-induced Ca-i(2+) rise stimulated the activity of the Na+/H + exchanger in HT29 cells. Our results indicate that a previously uncharact erized extracellular, G protein-coupled, Zn2+-sensing receptor is functiona l in colonocytes. Because Ca-i(2+) rise is known to regulate key cellular a nd signal-transduction processes, the zinc-sensing receptor may provide the missing link between extracellular zinc concentration changes and the regu lation of cellular processes.