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Monitoring ER/SR Calcium Release with the Targeted Ca2+ Sensor CatchER+
Published on: May 19, 2017
Redox regulation of sodium and calcium handling
Stefan Wagner1, Adam G Rokita, Mark E Anderson
1Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum für Herzkreislaufforschung, Georg-August-Universität, Göttingen, Germany.
Insights
Reactive oxygen species (ROS) can activate stress kinases, disrupting intracellular calcium handling in heart failure (HF). Understanding ROS signaling versus damage is key for developing targeted HF treatments.
Area of Science:
- Cardiovascular Physiology
- Cellular Signaling
- Biochemistry
Background:
- Heart failure (HF) involves impaired intracellular calcium (Ca) handling, leading to contractile dysfunction and arrhythmias.
- Activated stress kinases, including cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), are implicated in HF pathogenesis.
- Reactive oxygen species (ROS) can directly oxidize and activate these kinases, offering an alternative pathway to classical activation.
Purpose of the Study:
- To elucidate the role of ROS-activated stress kinases in the disturbed cellular Ca homeostasis observed in heart failure.
- To investigate how ROS mediate their effects on ion channels and transporters through stress kinase activation in HF.
- To differentiate between physiological ROS signaling and pathological ROS damage in the context of HF.
Main Methods:
- Investigated the mechanisms by which ROS influence kinase activity and Ca handling proteins.
- Examined the impact of ROS-induced Ca/calmodulin-dependent protein kinase II (CaMKII) activation on Na influx and Ca handling.
- Analyzed the consequences of ROS-induced sarcoplasmic reticulum dysfunction on intracellular Ca levels.
Main Results:
- ROS can directly oxidize and activate stress kinases, contributing to altered Ca handling in HF.
- Oxidation and activation of CaMKII by ROS can increase Na influx, leading to Na accumulation and action potential prolongation.
- ROS-induced sarcoplasmic reticulum dysfunction, coupled with altered Ca entry, results in significant intracellular Ca accumulation, reduced contractility, and arrhythmias.
Conclusions:
- The interplay between ROS, stress kinases, and Ca handling proteins is central to HF pathophysiology.
- Distinguishing between ROS signaling and ROS-induced damage is critical for understanding HF development.
- Targeted therapeutic strategies may be developed by differentiating fine-tuned ROS signaling from unspecific ROS damage.
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.
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