Phospholipase C-mediated regulation of transient receptor potential vanilloid 6 channels: implications in active intestinal Ca2+ 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 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.
Thyagarajan
Baskaran
B
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
Benn
Bryan S
BS
Christakos
Sylvia
S
Rohacs
Tibor
T
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D002460:Cell Line; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D004963:Estrenes; D019269:Phosphatidylinositol 4,5-Diphosphate; D010742:Phospholipid Ethers; D011760:Pyrrolidinones; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C026659:edelfosine; D010738:Type C Phospholipases; D002118:Calcium