Phospholipase C-Mediated Regulation of Transient Receptor Potential Vanilloid 6 Channels: Implications in Active Intestinal Ca2+ Transport

摘要

Transient receptor potential vanilloid 6 (TRPV6) channels play an important role in intestinal Ca2+ transport. These channels undergo Ca2+-induced inactivation. Here we show that Ca2+ flowing through these channels activates phospholipase C (PLC) leading to the depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) and formation of inositol 1,4,5-trisphosphate in TRPV6-expressing cells. PIP2 depletion was inhibited by the two structurally different PLC inhibitors 1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) and edelfosine. Ca2+-induced inactivation of TRPV6 was also prevented by the PLC inhibitors in whole-cell patch-clamp experiments. Ca2+ signals in TRPV6-expressing cells were transient upon restoration of extracellular Ca2+ but were rendered more sustained by the PLC inhibitors. Finally, intestinal Ca2+ transport in the everted duodenal sac assay was enhanced by edelfosine. These observations suggest that Ca2+-induced inactivation of TRPV6 limits intestinal Ca2+ absorption and raise the possibility that Ca2+ absorption can be enhanced pharmacologically by interfering with PLC activation.