A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice

Dirksen, Wessel P.; Lacombe, Véronique A.; Chi, Mei; Kalyanasundaram, Anuradha; Viatchenko‐Karpinski, Serge; Terentyev, Dmitry; Zhou, Zikang; Vedamoorthyrao, Srikanth; Li, Ning; Chiamvimonvat, Nipavan; Carnes, Cynthia A.; Franzini‐Armstrong, Clara; Györke, Sándor; Periasamy, Muthu

doi:10.1016/j.cardiores.2007.03.002

Cited by 54 publications

(60 citation statements)

References 45 publications

(47 reference statements)

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“…One such protein is RyR2, where specific mutations result in a leaky RyR Ca 2+ release channel that can result in arrhythmiagenesis under stress conditions (Jiang et al, 2002;George et al, 2003;Lehnart et al, 2004;Kannankeril et al, 2006;Liu et al, 2006). Another series of mutations in calsequestrin (CSQ2) have been shown to induce leaky Ca 2+ release from the SR that is mediated at least in part by induction of increased RyR2 expression (Terentyev et al, 2003;di Barletta et al, 2006;Terentyev et al, 2006;Dirksen et al, 2007;Song et al, 2007). The role of CSQ in control of SR Ca 2+ release is emphasized by findings that overexpression of CSQ results in reduced Ca 2+ spark frequency and co-ordination, mirroring the effect of CSQ mutations on SR Ca 2+ release .…”

Section: Differential Properties Of Ca 2+ Sparks In Cardiac and Skelementioning

confidence: 99%

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Weisleder

2008

Ageing Research Reviews

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Ca 2+ sparks are the fundamental units that comprise Ca 2+ -induced Ca 2+ release (CICR) in striated muscle cells. In cardiac muscle, spontaneous Ca 2+ sparks underlie the rhythmic CICR activity during heart contraction. In skeletal muscle, Ca 2+ sparks remain quiescent during the resting state and are activated in a plastic fashion to accommodate various levels of stress. With aging, the plastic Ca 2+ spark signal becomes static in skeletal muscle, whereas loss of CICR control leads to leaky Ca 2+ spark activity in aged cardiomyocytes. Ca 2+ spark responses reflect the integrated function of the intracellular Ca 2+ regulatory machinery centered around the triad or dyad junctional complexes of striated muscles, which harbor the principal molecular players of excitation-contraction coupling. This review highlights the contribution of age-related modification of the Ca 2+ release machinery and the effect of membrane structure and membrane cross-talk on the altered Ca 2+ spark signaling during aging of striated muscles.

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Section: Differential Properties Of Ca 2+ Sparks In Cardiac and Skelementioning

confidence: 99%

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Weisleder

2008

Ageing Research Reviews

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Section: Methodsmentioning

confidence: 99%

“…Ventricular myocytes were isolated from CASQ2 D307H , CASQ2 null, and WT hearts by enzyme digestion, as before (4). Transmembrane ionic currents were recorded by whole cell patch-clamp experiments, as described previously (4). Experiments were performed either in patch-clamped or in permeabilized myocytes at room temperature (21 to 23°C) Whole cell patch-clamp recordings of transmembrane currents were performed using an Axopatch 200B amplifier (Axon Instruments) and pClamp-9 software.…”

Section: Methodsmentioning

confidence: 99%

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Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background

Kalyanasundaram

Viatchenko‐Karpinski

Belevych

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The role of calsequestrin (CASQ2) in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) transport has gained significant attention since point mutations in CASQ2 were reported to cause ventricular arrhythmia. In the present study, we have critically evaluated the functional consequences of expressing the CASQ2D307H mutant protein in the CASQ2 null mouse. We recently reported that the mutant CASQ2D307H protein can be stably expressed in CASQ2 null hearts, and it targets appropriately to the junctional SR (Kalyanasundaram A, Bal NC, Franzini-Armstrong C, Knollmann BC, Periasamy M. J Biol Chem 285: 3076–3083, 2010). In this study, we found that introduction of CASQ2D307H protein in the CASQ2 null background partially restored triadin 1 levels, which were decreased in the CASQ2 null mice. Despite twofold expression (relative to wild-type CASQ2), the mutant protein failed to increase SR Ca2+ load. We also found that the Ca2+ transient decays slower in the CASQ2 null and CASQ2D307H cells. CASQ2D307H myocytes, when rhythmically paced and challenged with isoproterenol, exhibit spontaneous Ca2+ waves similar to CASQ2 null myocytes; however, the stability of Ca2+ cycling was increased in the CASQ2D307H myocytes. In the presence of isoproterenol, Ca2+-transient amplitude in CASQ2D307H myocytes was significantly decreased, possibly indicating an inherent defect in Ca2+ buffering capacity and release from the mutant CASQ2 at high Ca2+ concentrations. We also observed polymorphic ventricular tachycardia in the CASQ2D307H mice, although lesser than in the CASQ2 null mice. These data suggest that CASQ2D307H point mutation may affect Ca2+ buffering capacity and Ca2+ release. We propose that poor interaction between CASQ2D307H and triadin 1 could affect ryanodine receptor 2 stability, thereby increasing susceptibility to delayed afterdepolarizations and triggered arrhythmic activity.

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“…There are, however, many questions raised by this investigation that motivate future work. Previous studies did show expression of the mutant CASQ2 protein, but they demonstrated that the D307H mutation impairs monomeric CASQ2 binding to triadin or/and disrupts formation of polymeric CASQ2 (45)(46)(47). This loss of CASQ2 function in animals with the D307H mutation may accelerate CASQ2 protein degradation, and the disparities in CASQ2 abundance may depend on differences in the genetic background of the mice used in the various studies.…”

Section: Complexities In Casq2 Investigations and Future Studiesmentioning

confidence: 99%

Chain-reaction Ca2+ signaling in the heart

Györke

Hagen²,

Terentyev³

et al. 2007

J. Clin. Invest.

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A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice

Abstract: The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.

Cited by 54 publications

References 45 publications

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background

Chain-reaction Ca2+ signaling in the heart

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A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice

Abstract: The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.

Cited by 54 publications

References 45 publications

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Functional consequences of stably expressing a mutant calsequestrin (CASQ2D307H) in the CASQ2 null background

Chain-reaction Ca2+ signaling in the heart

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Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background