title: Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Swapnil K
authors.initials: SK
authors.lastname: Sonkusare
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Bonev
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ledoux
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.forename: Michael I
authors.initials: MI
authors.lastname: Kotlikoff
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Heppner
authors.forename: David C
authors.initials: DC
authors.lastname: Hill-Eubanks
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D015640:Ion Channel Gating; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D011976:Receptors, Muscarinic; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D007930:Leucine; D002118:Calcium