Transient receptor potential vanilloid 6 (TRPV6) channels play an important role in intestinal Ca 2+ transport. These channels undergo Ca 2+ -induced inactivation. Here we show that Ca 2+ flowing through these channels activates phospholipase C (PLC) leading to the depletion of phosphatidyl-inositol 4,5-bisphosphate (PIP 2) and formation of inositol 1,4,5-trisphosphate in TRPV6-expressing cells. PIP 2 depletion was inhibited by the two structurally different PLC inhibitors 1 -[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U73122) and edelfosine. Ca 2+ -induced inac tivation of TRPV6 was also prevented by the PLC inhibitors in whole-cell patch-clamp experiments. Ca 2+ signals in TRPV6-expressing cells were transient upon restoration of extracellular Ca 2+ but were rendered more sustained by the PLC inhibitors. Finally, intestinal Ca 2+ transport in the everted duodenal sac assay was enhanced by edelfosine. These observations suggest that Ca 2+-induced inactivation of TRPV6 limits intestinal Ca 2+ absorption and raise the possibility that Ca 2+ absorption can be enhanced pharmacologically by interfering with PLC activation.