Phospholipase C-mediated regulation of transient receptor potential vanilloid 6 channels: implications in active intestinal Ca ²⁺ transport

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.