Phospholipase C-mediated regulation of transient receptor potential vanilloid 6 channels: implications in active intestinal Ca2+ transport

Mol Pharmacol. 2009 Mar;75(3):608-16. doi: 10.1124/mol.108.052449. Epub 2008 Dec 10.

Abstract

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 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / physiology
  • Calcium / antagonists & inhibitors
  • Calcium / physiology*
  • Calcium Channels / physiology*
  • Cell Line
  • Estrenes / pharmacology
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 4,5-Diphosphate / biosynthesis
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phospholipid Ethers / pharmacology
  • Pyrrolidinones / pharmacology
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / physiology*
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / physiology*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Calcium Channels
  • Estrenes
  • Phosphatidylinositol 4,5-Diphosphate
  • Phospholipid Ethers
  • Pyrrolidinones
  • TRPV Cation Channels
  • TRPV6 protein, human
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • edelfosine
  • Type C Phospholipases
  • Calcium