Document Detail


Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5.
MedLine Citation:
PMID:  22843785     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I(Kur) current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox-sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress.
OBJECTIVE: To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5.
METHODS AND RESULTS: Labeling studies with the sulfenic acid-specific probe DAz and horseradish peroxidase-streptavidin Western blotting demonstrated a global increase in sulfenic acid-modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole-cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress.
CONCLUSIONS: Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases.
Authors:
Laurie K Svoboda; Khalilah G Reddie; Lian Zhang; Eileen D Vesely; Elizabeth S Williams; Sarah M Schumacher; Ryan P O'Connell; Robin Shaw; Sharlene M Day; Justus M Anumonwo; Kate S Carroll; Jeffrey R Martens
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-27
Journal Detail:
Title:  Circulation research     Volume:  111     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-17     Completed Date:  2013-01-11     Revised Date:  2013-09-17    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  842-53     Citation Subset:  IM    
Affiliation:
Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109-5632, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Atrial Fibrillation / metabolism*,  pathology
Case-Control Studies
Cell Line
Cells, Cultured
Humans
Kv1.5 Potassium Channel / chemistry*,  metabolism*
Mice
Models, Animal
Molecular Sequence Data
Myocardium / metabolism*
Myocytes, Cardiac / metabolism,  pathology
Oxidation-Reduction
Oxidative Stress / physiology
Rats
Reactive Oxygen Species
Signal Transduction / physiology
Sulfenic Acids / metabolism*
Grant Support
ID/Acronym/Agency:
HL0270973/HL/NHLBI NIH HHS; R01 GM102187/GM/NIGMS NIH HHS; R01 HL070973/HL/NHLBI NIH HHS; R01 HL093338-01/HL/NHLBI NIH HHS; T32ES07062/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Kv1.5 Potassium Channel; 0/Reactive Oxygen Species; 0/Sulfenic Acids
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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