Reactive oxygen species impair Slo1 BK channel function by altering cysteine-mediated calcium sensing.
Vascular dysfunction is a hallmark of many diseases, including coronary heart disease, stroke and diabetes. The underlying mechanisms of these disorders, which are intimately associated with inflammation and oxidative stress caused by excess reactive oxygen species (ROS), have remained elusive. Here we report that ROS are powerful inhibitors of vascular smooth muscle calcium-dependent Slo1 BK or Maxi-K potassium channels, an important physiological determinant of vascular tone. By targeting a cysteine residue near the Ca(2+) bowl of the BK alpha subunit, H(2)O(2) virtually eliminates physiological activation of the channel, with an inhibitory potency comparable to a knockout of the auxiliary subunit BK beta 1. These results reveal a molecular structural basis for the vascular dysfunction involving oxidative stress and provide a solid rationale for a potential use of BK openers in the prevention and treatment of cardiovascular disorders.
Tang
Xiang Dong
XD
Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
Garcia
Maria L
ML
Heinemann
Stefan H
SH
Hoshi
Toshinori
T
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D003545:Cysteine / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation; D017382:Reactive Oxygen Species; D017386:Sequence Homology, Amino Acid
D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D003545:Cysteine; D002118:Calcium