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(i)2+ release was zinc specific and could not be triggered by other heavy metals. Furthermore, zinc failed to activate the Ca(2+)-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 uncharacterized extracellular, G protein-coupled, Zn(2+)-sensing receptor is functional in colonocytes. Because Ca(i)2+ 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.
Hershfinkel
M
M
Department of Physiology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Moran
A
A
Grossman
N
N
Sekler
I
I
D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D003110:Colonic Neoplasms; D004963:Estrenes / Q000494:pharmacology; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney; D007700:Kinetics; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D015032:Zinc / Q000502:physiology*
D004963:Estrenes; D005452:Fluoresceins; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C057433:2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester; D010738:Type C Phospholipases; D015032:Zinc; D002118:Calcium