Oxidative stress inhibits vascular K(ATP) channels by S-glutathionylation

J Biol Chem. 2010 Dec 3;285(49):38641-8. doi: 10.1074/jbc.M110.162578. Epub 2010 Oct 6.


The K(ATP) channel is an important player in vascular tone regulation. Its opening and closure lead to vasodilation and vasoconstriction, respectively. Such functions may be disrupted in oxidative stress seen in a variety of cardiovascular diseases, while the underlying mechanism remains unclear. Here, we demonstrated that S-glutathionylation was a modulation mechanism underlying oxidant-mediated vascular K(ATP) channel regulation. An exposure of isolated mesenteric rings to hydrogen peroxide (H(2)O(2)) impaired the K(ATP) channel-mediated vascular dilation. In whole-cell recordings and inside-out patches, H(2)O(2) or diamide caused a strong inhibition of the vascular K(ATP) channel (Kir6.1/SUR2B) in the presence, but not in the absence, of glutathione (GSH). Similar channel inhibition was seen with oxidized glutathione (GSSG) and thiol-modulating reagents. The oxidant-mediated channel inhibition was reversed by the reducing agent dithiothreitol (DTT) and the specific deglutathionylation reagent glutaredoxin-1 (Grx1). Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester (BioGEE) showed incorporation of GSH to the Kir6.1 subunit in the presence of H(2)O(2). These results suggest that S-glutathionylation is an important mechanism for the vascular K(ATP) channel modulation in oxidative stress.

Publication types

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

MeSH terms

  • Animals
  • Cardiovascular Diseases / metabolism
  • Dithiothreitol / pharmacology
  • Glutaredoxins / metabolism
  • Glutaredoxins / pharmacology
  • Glutathione Disulfide / metabolism*
  • Glutathione Disulfide / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • KATP Channels
  • Male
  • Mesenteric Arteries / metabolism*
  • Oxidants / pharmacology
  • Oxidative Stress*
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Vasodilation / drug effects
  • Vasodilation / physiology


  • Glutaredoxins
  • KATP Channels
  • Oxidants
  • Potassium Channels, Inwardly Rectifying
  • uK-ATP-1 potassium channel
  • Hydrogen Peroxide
  • Dithiothreitol
  • Glutathione Disulfide