Calcium Leak Through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia (original) (raw)
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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, 2010
Mutations in the cardiac ryanodine receptor Ca 2þ release channel, RyR2, underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited life-threatening arrhythmia. CPVT is triggered by spontaneous RyR2mediated sarcoplasmic reticulum (SR) Ca 2þ release in response to SR Ca 2þ overload during b-adrenergic stimulation. However, whether elevated SR Ca 2þ content-in the absence of protein kinase A activation-affects RyR2 function and arrhythmogenesis in CPVT remains elusive.
Arrhythmogenic mechanisms in ryanodine receptor channelopathies
Science China Life Sciences, 2014
Ryanodine receptors (RyRs) are the calcium release channels of sarcoplasmic reticulum (SR) that provide the majority of calcium ions (Ca 2+) necessary to induce contraction of cardiac and skeletal muscle cells. In their intracellular environment, RyR channels are regulated by a variety of cytosolic and luminal factors so that their output signal (Ca 2+) induces finely-graded cell contraction without igniting cellular processes that may lead to aberrant electrical activity (ventricular arrhythmias) or cellular remodeling. The importance of RyR dysfunction has been recently highlighted with the demonstration that point mutations in RYR2, the gene encoding for the cardiac isoform of the RyR (RyR2), are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic syndrome characterized by the development of adrenergically-mediated ventricular tachycardia in individuals with an apparently normal heart. Here we summarize the state of the field in regards to the main arrhythmogenic mechanisms triggered by RyR2 channels harboring mutations linked to CPVT. Most CPVT mutations characterized to date endow RyR2 channels with a gain of function, resulting in hyperactive channels that release Ca 2+ spontaneously, especially during diastole. The spontaneous Ca 2+ release is extruded by the electrogenic Na + /Ca 2+ exchanger, which depolarizes the external membrane (delayed afterdepolarization or DAD) and may trigger untimely action potentials. However, a rare set of CPVT mutations yield RyR2 channels that are intrinsically hypo-active and hypo-responsive to stimuli, and it is unclear whether these channels release Ca 2+ spontaneously during diastole. We discuss novel cellular mechanisms that appear more suitable to explain ventricular arrhythmias due to RyR2 loss-of-function mutations.
Canadian Journal of Cardiology, 2013
Mutations in ryanodine receptor 2 (RYR2) gene can cause catecholaminergic polymorphic ventricular tachycardia (CPVT). The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. The mutation has been functionally characterized via storeoverload-induced Ca 2þ release (SOICR) and tritium-labelled ryanodine ([ 3 H]ryanodine) binding assays. The S4153R mutation enhanced propensity for spontaneous Ca 2þ release and reduced SOICR threshold but did not alter Ca 2þ activation of [ 3 H]ryanodine binding, a common feature of other CPVT gain-of-function RYR2 mutations. We conclude that the S4153R mutation is a gain-of-function RYR2 mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation. R ESUM E Les mutations du gène du r ecepteur de la ryanodine de type 2 (RyR2) peuvent causer une tachycardie ventriculaire polymorphe cat echolaminergique (TVPC). La nouvelle mutation du RyR2-S4153R serait une cause de TVPC et de fibrillation auriculaire. La mutation a et e fonctionnellement caract eris ee par la lib eration de Ca 2þ induite par une surcharge du stock calcique (SOICR : store-overload-induced Ca 2þ release) et les analyses de liaison de la ryanodine marqu ee au tritium ([ 3 H]ryanodine). La mutation du S4153R a am elior e la propension à la lib eration spontan ee de Ca 2þ et a r eduit le seuil de SOICR, mais n'apas alt er el'activation de Ca 2þ de la liaison [ 3 H]ryanodine, une caract eristique commune à d'autres mutations « gain de fonction » du RyR2 li ees à la TVPC. Nous concluons que la mutation du S4153R est une mutation « gain de fonction » du RyR2 associ ee au ph enotype clinique caract eris e par la TVPC et la fibrillation auriculaire.
Heart Rhythm, 2016
BACKGROUND Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are o300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP). OBJECTIVE The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP. METHODS Seven patients with scTdP (mean age 34 ± 12 years; 4 men and 3 women) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods; variant minor allele frequency was confirmed in 3 databases; and the pathogenicity was investigated in silico analysis using multiple tools. The activity of wild-type and mutant RyR2 channels was evaluated by monitoring Ca 2þ signals of HEK293 cells with a [ 3 H]ryanodine binding assay. RESULTS The mean coupling interval of PVCs was 282 ± 13 ms. The 12-lead electrocardiogram had no specific findings except PVCs with an extremely short-coupling interval. Genetic analysis revealed 3 novel RyR2 variants and 1 polymorphism, all located in the cytoplasmic region. p.Ser4938Phe was not detected in 3 databases, and in silico analysis indicated its pathogenicity. In functional analysis, p.Ser4938Phe demonstrated loss of function and impaired RyR2 channel Ca 2þ release, while 2 other variants, p.Val1024Ile and p.Ala2673Val, had mild gain-of-function effects but were similar to the polymorphism p.Asn1551Ser. CONCLUSION We identified an RyR2 variant associated with reduced Ca 2þ release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear.
Ryanodine receptor mutations in arrhythmia: The continuing mystery of channel dysfunction
FEBS Letters, 2010
Mutations in RyR2 are causative of an inherited disorder which often results in sudden cardiac death. Dysfunctional channel behaviour has been the subject of many investigations varying from single channel analysis through to complex animal models. This review discusses recent advances in the field, describes the controversy surrounding the exact consequences of RyR2 mutation and how the disparate data may be reconciled. This heterogeneity of function with respect to the effects of polymorphisms, phosphorylation, cytosolic and luminal Ca 2+ as well as inter-domain interactions may have important implications for the recent pharmaceutical therapies which have been put forward. We surmise that a comprehensive characterisation of mutations on a case-by-case basis may be beneficial for the development of specifically targeted therapies. (N.L. Thomas), williamsaj9@cardiff. ac.uk (A.J. Williams). FEBS Letters 584 (2010) 2153-2160 j o u r n a l h o m e p a g e : w w w . F E B S L e t t e r s . o r g * Diastolic conditions refers to 150 nM Ca 2+ and 1 mM Mg 2+ in the cis compartment with 53 mM trans Ca 2+ . ** Low Ca 2+ refers to symmetrical 45 nM buffered Ca 2+ .
Biochemical Society Transactions, 2007
The cardiac ryanodine receptor (RyR2) mediates rapid Ca2+ efflux from intracellular stores to effect myocyte contraction during the process of EC (excitation–contraction) coupling. It is now known that mutations in this channel perturb Ca2+ release function, leading to triggered arrhythmias that may cause SCD (sudden cardiac death). Resolving the precise molecular mechanisms by which SCD-linked RyR2 dysfunction occurs currently constitutes a burgeoning area of cardiac research. So far, defective channel phosphorylation, accessory protein binding, luminal/cytosolic Ca2+ sensing, and the disruption of interdomain interactions represent the main candidate mechanisms for explaining aberrant SR (sarcoplasmic reticulum) Ca2+ release via mutants of RyR2. It appears increasingly unlikely that a single exclusive common mechanism underlies every case of mutant channel dysfunction, and that each of these potential mechanisms may contribute to the resultant phenotype. The present review will co...
Circulation, 2014
Background— The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca 2+ leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca 2+ release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. Methods and Results— CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca 2+ release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca 2+ /calmodulin-dependent protein kinase II–mediated RyR2-S2814 phosphorylation in CREM...
Journal of Cellular Physiology, 2002
The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in “leaky” channels. SR calcium leak during diastole can generate “delayed after depolarizations” that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation. J. Cell. Physiol. 190: 1–6, 2002. © 2002 Wiley-Liss, Inc.