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lüll Phospholipase C-mediated regulation of transient receptor potential vanilloid 6 channels: implications in active intestinal Ca2+ transport Thyagarajan B; Benn BS; Christakos S; Rohacs TMol Pharmacol 2009[Mar]; 75 (3): 608-16Transient 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 phosphatidylinositol 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-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) and edelfosine. Ca(2+)-induced inactivation 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.|Animals[MESH]|Biological Transport, Active/drug effects/physiology[MESH]|Calcium Channels/*physiology[MESH]|Calcium/antagonists & inhibitors/*physiology[MESH]|Cell Line[MESH]|Estrenes/pharmacology[MESH]|Humans[MESH]|Intestinal Mucosa/drug effects/enzymology/*metabolism[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Phosphatidylinositol 4,5-Diphosphate/biosynthesis/metabolism[MESH]|Phospholipid Ethers/pharmacology[MESH]|Pyrrolidinones/pharmacology[MESH]|TRPV Cation Channels/antagonists & inhibitors/*physiology[MESH]|Type C Phospholipases/antagonists & inhibitors/*physiology[MESH]|Up-Regulation/drug effects/physiology[MESH] |