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.

Abstract-Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP 3 R)-mediated Ca 2ϩ release plays an important role in the modulation of excitation-contraction coupling (ECC) in atrial tissue and the generation of arrhythmias, specifically chronic atrial fibrillation (AF). IP 3 R type-2 (IP 3 R2) is the predominant IP 3 R isoform expressed in atrial myocytes. To determine the role of IP 3 R2 in atrial arrhythmogenesis and ECC, we generated IP 3 R2-deficient mice. Our results revealed that endothelin-1 (ET-1) stimulation of wild-type (WT) atrial myocytes caused an increase in basal [Ca 2ϩ ] i , an enhancement of action potential (AP)-induced [Ca 2ϩ ] i transients, an improvement of the efficacy of ECC (increased fractional SR Ca 2ϩ release), and the occurrence of spontaneous arrhythmogenic Ca 2ϩ release events as the result of activation of IP 3 R-dependent Ca 2ϩ release. In contrast, ET-1 did not alter diastolic [Ca 2ϩ ] i or cause spontaneous Ca 2ϩ release events in IP 3 R2-deficient atrial myocytes. Under basal conditions the spatio-temporal properties (amplitude, rise-time, decay kinetics, and spatial spread) of [Ca 2ϩ ] i transients and fractional SR Ca 2ϩ release were not different in WT and IP 3 R2-deficient atrial myocytes. WT and IP 3 R2-deficient atrial myocytes also showed a significant and very similar increase in the amplitude of AP-dependent [Ca 2ϩ ] i transients and Ca 2ϩ spark frequency in response to isoproterenol stimulation, suggesting that both cell types maintained a strong inotropic reserve. No compensatory changes in Ca 2ϩ regulatory protein expression (IP 3 R1, IP 3 R3, RyR2, NCX, SERCA2) or morphology of the atria could be detected between WT and IP 3 R2-deficient mice. These results show that lack of IP 3 R2 abolishes the positive inotropic effect of neurohumoral stimulation with ET-1 and protects from its arrhythmogenic effects. (Circ Res. 2005;96:1274-1281.)Key Words: IP 3 receptor Ⅲ intracellular calcium Ⅲ atrial arrhythmias Ⅲ excitation-contraction coupling Ⅲ endothelin C hronic atrial fibrillation (AF) is the most common sustained form of cardiac arrhythmia. AF is characterized by an atrial activation rate of typically Ͼ400 beats per minute, and is associated with 2 major complications including cardiac dysfunction and thrombus formation, resulting in an increased risk of morbidity because of heart failure and stroke. 1,2 In recent years, considerable attention has focused on the cellular and molecular mechanisms involved in AF (for review see Nattel 3,4 activates the RyR which leads to massive Ca 2ϩ release from the SR by a mechanism known as Ca 2ϩ -induced Ca 2ϩ release (CICR 12 ), which is required for inducing contraction.Cardiac myocytes also contain IP 3 R channels, however their functional importance in the heart has remained controversial. IP 3 Rs release Ca 2ϩ from intracellular Ca 2ϩ stores when activated by IP 3 , a product generated by phospholipase C (PLC) metabolism of phosphoinositol-4,5-bisphosphate (PIP 2 ) in response to G-protein-c...

Inositol‐1,4,5‐trisphosphate (IP3)‐dependent Ca2+ release represents the major Ca2+ mobilizing pathway responsible for diverse functions in non‐excitable cells. In the heart, however, its role is largely unknown or controversial. In intact cat atrial myocytes, endothelin (ET‐1) increased basal [Ca2+]i levels, enhanced action potential‐evoked [Ca2+]i transients, caused [Ca2+]i transients with alternating amplitudes (Ca2+ alternans), and facilitated spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in the form of Ca2+ sparks and arrhythmogenic Ca2+ waves. These effects were prevented by the IP3 receptor (IP3R) blocker aminoethoxydiphenyl borate (2‐APB), suggesting the involvement of IP3‐dependent SR Ca2+ release. In saponin‐permeabilized myocytes IP3 and the more potent IP3R agonist adenophostin increased basal [Ca2+]i and the frequency of spontaneous Ca2+ sparks. In the presence of tetracaine to eliminate Ca2+ release from ryanodine receptor (RyR) SR Ca2+ release channels, IP3 and adenophostin triggered unique elementary, non‐propagating IP3R‐dependent Ca2+ release events with amplitudes and kinetics that were distinctly different from classical RyR‐dependent Ca2+ sparks. The effects of IP3 and adenophostin were prevented by heparin and 2‐APB. The data suggest that IP3‐dependent Ca2+ release increases [Ca2+]i in the vicinity of RyRs and thus facilitates Ca2+‐induced Ca2+ release during excitation–contraction coupling. It is concluded that in the adult mammalian atrium IP3‐dependent Ca2+ release enhances atrial Ca2+ signalling and exerts a positive inotropic effect. In addition, by facilitating Ca2+ release, IP3 may also be an important component in the development of Ca2+‐mediated atrial arrhythmias.