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.

FIG. 1.

Sources of ROS in heart failure, and potential pathways for ROS-dependent oxidative regulation of target proteins. Left panel: indirect pathway with activation of serine/threonine kinases by oxidation, which in turn phosphorylate target proteins. Right panel: direct pathway with oxidation of target proteins. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 2.

Schematic structure of CaMKII and activation pathways. Upper panel: Schematic depiction of the CaMKII holoenzyme that consists of two stacked hexameric rings (upper right), each ring consisting of six subunits (upper left) which contain the association domain, regulatory domain, and catalytic domain (lower left). Lower panel: Possible ways of CaMKII activation by Ca/CaM that lead to Ca²⁺ and calmodulin- autonomous activity: by intersubunit autophosphorylation of threonine 286 and/or methionine 281/282 oxidation. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 3.

Overview of known and putative ROS effects by direct oxidation of proteins of the excitation–contraction coupling. CaMKII, Ca/CaM dependent protein kinase II; NCX, Na/Ca-exchanger; OX, activation by oxidation; PKA, proteinkinase A; PKC, proteinkinase C; PLB, phospholamban; RyR, ryanodin receptor; SERCA, SR Ca ATPase; Trop I, troponin I. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 4.

Overview of known and putative ROS effects on Na and Ca handling proteins that may be mediated by ROS-activated CaMKII (A), ROS-activated PKA (B), and ROS-activated PKC (C). (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 5.

Effects of ROS-activated CaMKII on pathological, proarrhythmic, membrane excitability. ROS-activated CaMKII leads to increased intracellular [Na] by increasing late I_Na (upper panel). This leads to prolongation of the action potential duration, early after depolarizations (EADs), and delayed afterdepolarizations (DADs, lower panel). The possible contributions of PKA and PKC are still unknown. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 6.

Effects of the ROS-mediated increase in intracellular Na on Ca transients and contractility. Increased intracellular Na disables the Ca extruding capacity of the Na^/Ca exchanger (NCX) and favors ‘reverse mode’ of the NCX, which increases intracellular and diastolic Ca and contributes to diastolic dysfunction. Increased SR Ca leak leads to reduced SR Ca load and reduced contractility, and also contributes to increased intracellular Ca. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)