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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism*
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Calcium Signaling*
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism*
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Endothelial Cells / physiology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / physiology
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Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
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Ion Channel Gating
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Leucine / analogs & derivatives
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Leucine / pharmacology
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Mesenteric Arteries / drug effects
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Mesenteric Arteries / metabolism*
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Mesenteric Arteries / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Patch-Clamp Techniques
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Receptors, Muscarinic / metabolism
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Signal Transduction
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Small-Conductance Calcium-Activated Potassium Channels / metabolism
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Sulfonamides / pharmacology
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TRPV Cation Channels / agonists
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TRPV Cation Channels / antagonists & inhibitors
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TRPV Cation Channels / metabolism*
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Vasodilation*
Substances
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Intermediate-Conductance Calcium-Activated Potassium Channels
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N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
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Receptors, Muscarinic
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Small-Conductance Calcium-Activated Potassium Channels
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Sulfonamides
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TRPV Cation Channels
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Trpv4 protein, mouse
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Leucine
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Calcium