Ryanodine Receptor-Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model (original) (raw)
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2014
Schmitz, Frank U. Müller, Miguel Valderrabano, Stanley Nattel, Dobromir Dobrev and Xander Respress, Sameer Ather, Darlene G. Skapura, Valerie K. Jordan, Frank T. Horrigan, Wilhelm Na Li, David Y. Chiang, Sufen Wang, Qiongling Wang, Liang Sun, Niels Voigt, Jonathan L. Atrial Fibrillation Substrate in a Transgenic Mouse Model Mediated Calcium Leak Drives Progressive Development of an − Ryanodine Receptor Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2014 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation doi: 10.1161/CIRCULATIONAHA.113.006611 2014;129:1276-1285; originally published online January 7, 2014; Circulation. http://circ.ahajournals.org/content/129/12/1276 World Wide Web at: The online version of this article, along with updated information and services, is located on the http://circ.ahajournals.org/content/suppl/2014/01/07/CIRCULATIONAHA.113.006611.DC1.html Da...
Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice
Journal of Clinical Investigation, 2009
Atrial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca 2+ handling. Diastolic Ca 2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2 R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice.
Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation
Circulation, 2005
Background-Ca 2ϩ leak from the sarcoplasmic reticulum (SR) may play an important role in triggering and/or maintaining atrial arrhythmias, including atrial fibrillation (AF). Protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2) resulting in dissociation of the channel-stabilizing subunit calstabin2 (FK506-binding protein or FKBP12.6) causes SR Ca 2ϩ leak in failing hearts and can trigger fatal ventricular arrhythmias. Little is known about the role of RyR2 dysfunction in AF, however. Methods and Results-Left and right atrial tissue was obtained from dogs with AF induced by rapid right atrial pacing (nϭ6 for left atrial, nϭ4 for right atrial) and sham instrumented controls (nϭ6 for left atrial, nϭ4 for right atrial). Right atrial tissue was also collected from humans with AF (nϭ10) and sinus rhythm (nϭ10) and normal cardiac function. PKA phosphorylation of immunoprecipitated RyR2 was determined by back-phosphorylation and by immunoblotting with a phosphospecific antibody. The amount of calstabin2 bound to RyR2 was determined by coimmunoprecipitation. RyR2 channel currents were measured in planar lipid bilayers. Atrial tissue from both the AF dogs and humans with chronic AF showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel. Channels isolated from dogs with AF exhibited increased open probability under conditions simulating diastole compared with channels from control hearts, suggesting that these AF channels could predispose to a diastolic SR Ca 2ϩ leak. Conclusions-SR Ca 2ϩ leak due to RyR2 PKA hyperphosphorylation may play a role in initiation and/or maintenance of AF.
Cardiovascular Research, 2011
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity and mortality. It causes profound changes in sarcoplasmic reticulum (SR) Ca 2+ homeostasis, including ryanodine receptor channel dysfunction and diastolic SR Ca 2+ leak, which might contribute to both decreased contractile function and increased propensity to atrial arrhythmias. In this review, we will focus on the molecular basis of ryanodine receptor channel dysfunction and enhanced diastolic SR Ca 2+ leak in AF. The potential relevance of increased incidence of spontaneous SR Ca 2+ release for both AF induction and/or maintenance and the development of novel mechanismbased therapeutic approaches will be discussed.
Cardiovascular Research, 2014
Altered Ca 2+ handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP1 on different subcellular targets such as ryanodine receptor type 2 (RyR2), especially in AF.
Circulation, 2010
Background Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca 2+ release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca 2+ remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca 2+ /calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and Results Mice in which the S2814 Ca 2+ /calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca 2+ release events, resulting in reduced sarcoplasmic reticulum Ca 2+ load on confocal microscopy. These Ca 2+ release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts wi...
Posttranslational modifications of cardiac ryanodine receptors: Ca2+ signaling and EC-coupling
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013
In cardiac muscle, a number of posttranslational protein modifications can alter the function of the Ca 2+ release channel of the sarcoplasmic reticulum (SR), also known as the ryanodine receptor (RyR). During every heartbeat RyRs are activated by the Ca 2+ -induced Ca 2+ release mechanism and contribute a large fraction of the Ca 2+ required for contraction. Some of the posttranslational modifications of the RyR are known to affect its gating and Ca 2+ sensitivity. Presently, research in a number of laboratories is focused on RyR phosphorylation, both by PKA and CaMKII, or on RyR modifications caused by reactive oxygen and nitrogen species (ROS/RNS). Both classes of posttranslational modifications are thought to play important roles in the physiological regulation of channel activity, but are also known to provoke abnormal alterations during various diseases. Only recently it was realized that several types of posttranslational modifications are tightly connected and form synergistic (or antagonistic) feed-back loops resulting in additive and potentially detrimental downstream effects. This review summarizes recent findings on such posttranslational modifications, attempts to bridge molecular with cellular findings, and opens a perspective for future work trying to understand the ramifications of crosstalk in these multiple signaling pathways. Clarifying these complex interactions will be important in the development of novel therapeutic approaches, since this may form the foundation for the implementation of multi-pronged treatment regimes in the future. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.