Abnormal Calcium Signaling and Sudden Cardiac Death Associated with Mutation of Calsequestrin

Serge Viatchenko-Karpinski, Dmitry Terentyev, Inna Györke, Radmila Terentyeva, Pompeo Volpe, Silvia G. Priori, Carlo Napolitano, Alessandra Nori, Simon C. Williams, Sandor Györke

Research output: Contribution to journalArticlepeer-review


Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation D307H (CASQ2D307H on Ca2+ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated ≈4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2 WT) or CASQ2D307H. Expression of CASQ2D307H reduced the Ca2+ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic ICa-induced Ca 2+ transients and of spontaneous Ca2+ sparks were reduced significantly in myocytes expressing CASQ2D307H. Myocytes expressing CASQ2D307H also displayed drastic disturbances of rhythmic oscillations in [Ca2+]i and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca2+ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2D307H mutation impairs SR Ca2+ storing and release functions and destabilizes the Ca 2+- induced Ca2+ release mechanism by reducing the effective Ca2+ buffering inside the SR and/or by altering the responsiveness of the Ca2+ release channel complex to luminal Ca 2+. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.

Original languageEnglish
Pages (from-to)471-477
Number of pages7
JournalCirculation Research
Issue number4
Publication statusPublished - Mar 5 2004


  • Calcium-induced calcium release
  • Calsequestrin
  • Catecholaminergic polymorphic ventricular tachycardia
  • Excitation-contraction coupling
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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