Elementary Ca2+ Signals Through Endothelial TRPV4 Channels Regulate Vascular Function

Science. 2012 May 4;336(6081):597-601. doi: 10.1126/science.1216283.

Abstract

Major features of the transcellular signaling mechanism responsible for endothelium-dependent regulation of vascular smooth muscle tone are unresolved. We identified local calcium (Ca(2+)) signals ("sparklets") in the vascular endothelium of resistance arteries that represent Ca(2+) influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a four-channel cluster was cooperative, with activation of as few as three channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small (SK)-conductance, Ca(2+)-sensitive potassium (K(+)) channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. These results support the concept that Ca(2+) influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high Ca(2+) sensitivity of IK and SK channels to cause vasodilation.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / physiology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
  • Ion Channel Gating
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / metabolism*
  • Mesenteric Arteries / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Receptors, Muscarinic / metabolism
  • Signal Transduction
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism
  • Sulfonamides / pharmacology
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / metabolism*
  • Vasodilation*

Substances

  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
  • Receptors, Muscarinic
  • Small-Conductance Calcium-Activated Potassium Channels
  • Sulfonamides
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Leucine
  • Calcium