Redox regulation of cardiac calcium channels and transporters

Abstract

Intracellular concentrations of redox-active molecules can significantly increase in the heart as a result of activation of specific signal transduction pathways or the development of certain pathophysiological conditions. Changes in the intracellular redox environment can affect many cellular processes, including the gating properties of ion channels and the activity of ion transporters. Because cardiac contraction is highly dependent on intracellular Ca(2+) levels ([Ca(2+)](i)) and [Ca(2+)](i) regulation, redox modification of Ca(2+) channels and transporters has a profound effect on cardiac function. The sarcoplasmic reticulum (SR) Ca(2+) release channel, or ryanodine receptor (RyR), is one of the well-characterized redox-sensitive ion channels in the heart. The redox modulation of RyR activity is mediated by the redox modification of sulfhydryl groups of cysteine residues. Other key components of cardiac excitation-contraction (e-c) coupling such as the SR Ca(2+) ATPase and L-type Ca(2+) channel are subject to redox modulation. Redox-mediated alteration of the activity of ion channels and pumps is directly involved in cardiac pathologies such as ischemia-reperfusion injury. Significant bursts of reactive oxygen species (ROS) generation occur during reperfusion of the ischemic heart, and changes in the activity of the major components of [Ca(2+)](i) regulation, such as RyR, Na(+)-Ca(2+) exchange and Ca(2+) ATPases, are likely to play an important role in ischemia-related Ca(2+) overload. This article summarizes recent findings on redox regulation of cardiac Ca(2+) transport systems and discusses contributions of this redox regulation to normal and pathological cardiac function.

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

“…The observation of NADH-induced ROS production in our study is consistent with others (27)(28)(29)(37)(38)(39). However, the mechanism is not well understood.…”

“…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.…”

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

“…superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1)(2)(3)(4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.…”

Dynamic Alterations in the CaV1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts

“…An increase in cytoplasmic Ca 2 + concentration in myocardial cells with hypoxia has been reported (Song et al, 2005;Liu et al, 2009), and intracellular Ca 2 + overload is an important cause for damage and dysfunction in the myocardium (Tang et al, 2011;Dhalla et al, 2012). As Ca V 1.2 is involved in the major route for Ca 2 + to enter into myocardial cells, the decreased expression of Ca V 1.2 and the overload of intracellular Ca 2 + seemed to be paradoxical, which suggests that intracellular Ca 2 + overload of MI may be related to other regulatory proteins of Ca V 1.2, such as Na + /Ca 2 + exchanger, Na + /H + exchanger, RyR, and SER-CA (Zima and Blatter, 2006;Vittone et al, 2008). CaMKII may regulate a variety of Ca 2 + -dependent proteins, such as LTCC, intracellular Ca 2 + release ryanodine receptor channels, and phospholamban (PLB).…”