The ryanodine receptor leak: how a tattered receptor plunges the failing heart into crisis

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Abstract
It has been persuasively shown in the last two decades that the development of heart failure is closely linked to distinct alterations in Ca2+ cycling. A crucial point in this respect is an increased spontaneous release of Ca2+ out of the sarcoplasmic reticulum during diastole via ryanodine receptors type 2 (RyR2). The consequence is a compromised sarcoplasmic reticulum Ca2+ storage capacity, which impairs systolic contractility and possibly diastolic cardiac function due to Ca2+ overload. Additionally, leaky RyR2 are more and more regarded to potently induce proarrhythmic triggers. Elimination of spontaneously released Ca2+ via RyR2 in diastole can cause a transient sarcolemmal inward current and hence delayed after depolarisations as substrate for cardiac arrhythmias. In this article, the pathological role and consequences of the SR Ca2+-leak and its regulation are reviewed with a main focus on protein kinase A and Ca2+-calmodulin-dependent kinase II. We summarise clinical consequences of “leaky RyR2” as well as possible therapeutic strategies in order to correct RyR2 dysfunction and discuss the significance of the available data.

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