title: Positive feedback regulation of agonist-stimulated endothelial Ca2+ dynamics by KCa3.1 channels in mouse mesenteric arteries.
abstract: OBJECTIVE
  Intermediate and small conductance KCa channels IK1 (KCa3.1) and SK3 (KCa2.3) are primary targets of endothelial Ca(2+) signals in the arterial vasculature, and their ablation results in increased arterial tone and hypertension. Activation of IK1 channels by local Ca(2+) transients from internal stores or plasma membrane channels promotes arterial hyperpolarization and vasodilation. Here, we assess arteries from genetically altered IK1 knockout mice (IK1(-/-)) to determine whether IK1 channels exert a positive feedback influence on endothelial Ca(2+) dynamics.
  
  
  RESULTS
  Using confocal imaging and custom data analysis software, we found that although the occurrence of basal endothelial Ca(2+) dynamics was not different between IK1(-/-) and wild-type mice (P>0.05), the frequency of acetylcholine-stimulated (2 μmol/L) Ca(2+) dynamics was greatly decreased in IK1(-/-) endothelium (515±153 versus 1860±319 events; P<0.01). In IK1(-/-)/SK3(T/T) mice, ancillary suppression (+Dox) or overexpression (-Dox) of SK3 channels had little additional effect on the occurrence of events under basal or acetylcholine-stimulated conditions. However, SK3 overexpression did restore the decreased event amplitudes. Removal of extracellular Ca(2+) reduced acetylcholine-induced Ca(2+) dynamics to the same level in wild-type and IK1(-/-) arteries. Blockade of IK1 and SK3 with the combination of charybdotoxin (0.1 μmol/L) and apamin (0.5 μmol/L) or transient receptor potential vanilloid 4 channels with HC-067047 (1 μmol/L) reduced acetylcholine Ca(2+) dynamics in wild-type arteries to the level of IK1(-/-)/SK3(T/T)+Dox arteries. These drug effects were not additive.
  
  
  CONCLUSIONS
  IK1, and to some extent SK3, channels exert a substantial positive feedback influence on endothelial Ca(2+) dynamics.
authors.affiliation: From the Department of Physiology, University of South Alabama College of Medicine, Mobile, AL (X.Q., M.F., V.S., M.L., M.S.T.); Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark (R.K.); and Translational Research Unit, University Hospital Miguel Servet, Aragon Institute of Health Sciences and ARAID, Zaragoza, Spain (R.K.).
authors.forename: Xun
authors.initials: X
authors.lastname: Qian
authors.forename: Michael
authors.initials: M
authors.lastname: Francis
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Solodushko
authors.forename: Mike
authors.initials: M
authors.lastname: Lin
authors.forename: Mark S
authors.initials: MS
authors.lastname: Taylor
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D025461:Feedback, Physiological; D005260:Female; D007091:Image Processing, Computer-Assisted; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000172:deficiency / Q000235:genetics; D012984:Software; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496900:Kcnn3 protein, mouse; C496925:Kcnn4 protein, mouse; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D014665:Vasodilator Agents; D000109:Acetylcholine
keywords: SK3 protein; TRPV4 protein; calcium; endothelium