Redox Regulation of Sodium and Calcium Handling

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.

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

“…The effects of increased cytosolic NADH on other Ca 2ϩ handling proteins are not completely understood, but modulation of these proteins by ROS is well established (39,51). The global impact of NCX inhibition by NADH on Ca 2ϩ homeostasis will depend on the overall effect of modifications on all of these proteins as well as on the pathological conditions responsible for the increased cytosolic NADH.…”

A change of heart: oxidative stress in governing muscle function?

“…Abnormalities in EC coupling components trigger and/or aggravate contractile dysfunction and growing evidence suggests an important role for redox modifications of key signalling components of EC coupling (Haycock et al 1996;Posterino and Lamb 1996;Gao et al 1996;Disatnik et al 1998;Duncan et al 2005;Dai et al 2007;Ullrich et al 2009;Canton et al 2014). The redox modification of protein kinase activity and direct effects on channels and ion transporters are well-known effects of ROS on ECC (Wagner et al 2013 (Viola et al 2007;Tang et al 2011). H 2 O 2 has been reported to be involved in the elevation of intracellular calcium concentration in a variety of cell types (Hu et al 1998;KrippeitDrews et al 1999;Redondo et al 2004).…”

Interleukin-1β-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats

“…The present data indicated that keratinocyte CD44 is also phosphorylated at this site and that the proportion of the phosphorylated form is reduced by the CAMKII inhibitor KN93, like in fibroblasts. The activity of CAMKII could be controlled via phosphorylation or phosphorylation-independent mechanisms, like oxidation, O-GlcNAc modification, and membrane targeting (53)(54)(55). Interestingly, the far end of the cytoplasmic tail of CD44 contains a PDZ binding domain, which binds phosphatases in other transmembrane molecules (Fig.…”