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Reactive oxygen species impair Slo1 BK channel function by altering cysteine-mediated calcium sensing
Xiang Dong Tang1, Maria L Garcia, Stefan H Heinemann
1Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
Abstract:
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.
Insights
Reactive oxygen species (ROS) inhibit vascular smooth muscle calcium-dependent potassium channels (BK channels), contributing to vascular dysfunction. Targeting these channels may offer new treatments for cardiovascular diseases.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Physiology
Background:
- Vascular dysfunction underlies diseases like coronary heart disease, stroke, and diabetes.
- Inflammation and oxidative stress from reactive oxygen species (ROS) are implicated but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of ROS in vascular smooth muscle dysfunction.
- To elucidate the molecular mechanisms by which ROS affect vascular tone via potassium channels.
Main Methods:
- Electrophysiological studies on vascular smooth muscle calcium-dependent Slo1 BK (or Maxi-K) potassium channels.
- Investigated the effect of hydrogen peroxide (H2O2) on channel activation.
- Examined the specific cysteine residue targeted by H2O2.
Main Results:
- ROS, specifically H2O2, were found to be potent inhibitors of Slo1 BK channels.
- H2O2 targets a cysteine residue near the Ca(2+) bowl of the BK alpha subunit.
- This inhibition significantly reduces physiological channel activation, comparable to beta 1 subunit knockout.
Conclusions:
- Reveals a molecular basis for vascular dysfunction linked to oxidative stress.
- Suggests that ROS directly impair BK channel function, impacting vascular tone.
- Provides a rationale for developing BK channel openers for cardiovascular disorder treatment and prevention.