Mind the store: modulating Ca(2+) reuptake with a leaky sarcoplasmic reticulum.

Abnormalities in cardiomyocyte intracellular calcium cycling, and specifically Ca2+ physiology of the sarcoplasmic reticulum (SR), in cardiac disease states have been an intense focus of research over the past 30 years. It is increasingly apparent that alterations of SR function may contribute to the pathophysiological changes observed in several cardiac diseases including chronic heart failure, acute ischemia-reperfusion injury, atrial fibrillation, and ventricular tachyarrhythmias. Increasingly, experimental evidence suggests that the role of SR Ca2+ cycling extends beyond the traditional biophysical control of cardiomyocyte contraction and relaxation, with SR Ca2+ cycling contributing to the regulation of hypertrophic signalling, mitochondrial energetics, cell survival pathways, protein folding, autophagy, and gene expression. Two changes to SR calcium physiology have been proposed to contribute to cardiac disease states: (i) abnormal SR Ca2+ uptake and (ii) abnormal SR calcium storage and release. Reported changes in endstage human failing hearts include reduced expression and activity of the SR Ca2+ ATPase 2a (SERCA2a), which slows Ca2+ reuptake and cardiomyocyte relaxation. Reduced SERCA2a activity also decreases the Ca2+ content of the SR, reducing the magnitude of Ca2+ release and contraction. In addition, the SR Ca2+ release channel, called the ryanodine receptor (RyR), becomes ‘leaky’ in failing cardiomyocytes. Suggested mechanisms include oxidative modification of the RyR, and greater RyR phosphorylation by Ca2+/ calmodulin-dependent protein kinase II (CaMKII) or protein kinase A. The resulting increased RyR open probability further contributes to reduce the SR Ca2+ content during heart failure (Figure 1A), and can promote triggered arrhythmias. Increased diastolic RyR opening is also believed to underlie arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia (CPVT), although in this disease the increased opening probability results from a mutation in the RyR or its associated SR calcium storage and RyR regulatory protein, calsequestrin, during phases of physiological or pharmacological stress. Until recently, CPVT has been considered an arrhythmogenic condition in the context of a structurally normal heart. However, the potential for increased diastolic SR Ca2+ leak alone to cause pathological remodelling, hypertrophy, and heart failure remained to be confirmed. This question is addressed by Kalyanasundaram et al. in the current issue of Cardiovascular Research. The authors elegantly show that an increased RyR leak is not only a key feature of the failing heart, but that increased RyR open probability, when combined with enhanced SR Ca2+ uptake, can also trigger disease development. This was achieved by cross-breeding calsequestrin knockout mice, which exhibit CPVT but not hypertrophy or heart failure, with either mice globally overexpressing the skeletal muscle SERCA1a isoform, or phospholamban knockout mice. The co-existence of enhanced SR Ca2+ uptake with a leaky RyR lead to exaggerated spontaneous SR Ca2+ release, apoptosis, and the development of hypertrophy, heart failure, and reduced survival. Several interesting discussion points arise from this work. The first concerns the role of SR-derived Ca2+ in triggering hypertrophy and disease progression. Hypertrophy is known to be triggered via the Ca2+-dependent calcineurin-NFAT signalling pathway (presumably through NFAT c3 and c4 isoforms), although the precise nature of the Ca2+ signal required to activate this pathway remains elusive. One possibility is that the system can sense an increase in the integrated Ca2+ transient, such as is known to occur during the early stages of heart failure when both Ca2+ current and SR Ca2+ release are enhanced. However, overexpression of SERCA2a or knockout of phospholamban, its endogenous inhibitor, do not trigger hypertrophy despite elevated Ca2+ transients. Alternatively, the NFAT pathway may be activated by an increase in diastolic [Ca2+], perhaps in the dyadic cleft where diffusion is limited. While speculative, support for this view comes from the observation that hypertrophy can be triggered by increasing trans-membrane Ca2+ entry via the L-type (but not T-type) Ca2+ channel or the Na+– Ca2+ exchanger. Under some circumstances, decreasing Ca2+ removal by reducing SERCA2a activity has also been associated with the activation of calcineurin signalling. Marked NFAT signalling and hypertrophy were recently reported in mice expressing low