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.

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Publisher Full Text

Authors

Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT

Institution

Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.

Source

Science (New York, N.Y.) 336:6081 2012 May 4 pg 597-601

MeSH

Animals
Calcium
Calcium Signaling
Endothelial Cells
Endothelium, Vascular
Intermediate-Conductance Calcium-Activated Potassium Channels
Ion Channel Gating
Leucine
Mesenteric Arteries
Mice
Mice, Inbred C57BL
Mice, Transgenic
Patch-Clamp Techniques
Receptors, Muscarinic
Signal Transduction
Small-Conductance Calcium-Activated Potassium Channels
Sulfonamides
TRPV Cation Channels
Vasodilation

Pub Type(s)

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

Language

eng

PubMed ID

22556255