title: The ryanodine receptor leak: how a tattered receptor plunges the failing heart into crisis.
abstract: It has been persuasively shown in the last two decades that the development of heart failure is closely linked to distinct alterations in Ca(2+) cycling. A crucial point in this respect is an increased spontaneous release of Ca(2+) out of the sarcoplasmic reticulum during diastole via ryanodine receptors type 2 (RyR2). The consequence is a compromised sarcoplasmic reticulum Ca(2+) storage capacity, which impairs systolic contractility and possibly diastolic cardiac function due to Ca(2+) overload. Additionally, leaky RyR2 are more and more regarded to potently induce proarrhythmic triggers. Elimination of spontaneously released Ca(2+) 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 Ca(2+)-leak and its regulation are reviewed with a main focus on protein kinase A and Ca(2+)-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.
authors.affiliation: Department of Cardiology and Pneumology, Heart Center, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
mesh_terms: D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003971:Diastole; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium