Redox regulation of sodium and calcium handling

Stefan Wagner, Adam G. Rokita, Mark Anderson, Lars S. Maier

Research output: Contribution to journalArticle

Abstract

Significance: In heart failure (HF), contractile dysfunction and arrhythmias result from disturbed intracellular Ca handling. Activated stress kinases like cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which are known to influence many Ca-regulatory proteins, are mechanistically involved. Recent Advances: Beside classical activation pathways, it is becoming increasingly evident that reactive oxygen species (ROS) can directly oxidize these kinases, leading to alternative activation. Since HF is associated with increased ROS generation, ROS-activated serine/threonine kinases may play a crucial role in the disturbance of cellular Ca homeostasis. Many of the previously described ROS effects on ion channels and transporters are possibly mediated by these stress kinases. For instance, ROS have been shown to oxidize and activate CaMKII, thereby increasing Na influx through voltage-gated Na channels, which can lead to intracellular Na accumulation and action potential prolongation. Consequently, Ca entry via activated NCX is favored, which together with ROS-induced dysfunction of the sarcoplasmic reticulum can lead to dramatic intracellular Ca accumulation, diminished contractility, and arrhythmias. Critical Issues: While low amounts of ROS may regulate kinase activity, excessive uncontrolled ROS production may lead to direct redox modification of Ca handling proteins. Therefore, depending on the source and amount of ROS generated, ROS could have very different effects on Ca-handling proteins. Future Directions: The discrimination between fine-tuned ROS signaling and unspecific ROS damage may be crucial for the understanding of heart failure development and important for the investigation of targeted treatment strategies.

Original languageEnglish (US)
Pages (from-to)1063-1077
Number of pages15
JournalAntioxidants and Redox Signaling
Volume18
Issue number9
DOIs
StatePublished - Mar 20 2013
Externally publishedYes

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Oxidation-Reduction
Reactive Oxygen Species
Sodium
Calcium
Phosphotransferases
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Heart Failure
Cyclic AMP-Dependent Protein Kinases
Cardiac Arrhythmias
Chemical activation
Proteins
Protein-Serine-Threonine Kinases
Sarcoplasmic Reticulum
Ion Channels
Protein Kinase C
Action Potentials
Homeostasis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

Redox regulation of sodium and calcium handling. / Wagner, Stefan; Rokita, Adam G.; Anderson, Mark; Maier, Lars S.

In: Antioxidants and Redox Signaling, Vol. 18, No. 9, 20.03.2013, p. 1063-1077.

Research output: Contribution to journalArticle

Wagner, Stefan ; Rokita, Adam G. ; Anderson, Mark ; Maier, Lars S. / Redox regulation of sodium and calcium handling. In: Antioxidants and Redox Signaling. 2013 ; Vol. 18, No. 9. pp. 1063-1077.
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