Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death

Dmitry Terentyev, Alessandra Nori, Massimo Santoro, Serge Viatchenko-Karpinski, Zuzana Kubalova, Inna Gyorke, Radmila Terentyeva, Srikanth Vedamoorthyrao, Nico A. Blom, Giorgia Valle, Carlo Napolitano, Simon C. Williams, Pompeo Volpe, Silvia G. Priori, Sandor Gyorke

Research output: Contribution to journalArticlepeer-review


Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca-signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2 in adult rat myocytes led to an increase in excitation-contraction coupling gain and to more frequent occurrences of spontaneous propagating (Ca waves) and local Ca signals (sparks) with respect to control cells expressing wild-type CASQ2 (CASQ2). As revealed by a Ca indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the increased occurrence of spontaneous Ca sparks and waves was associated with a dramatic decrease in intra-SR [Ca]. Recombinant CASQ2 and CASQ2 exhibited similar Ca-binding capacities in vitro; however, the mutant protein lacked the ability of its WT counterpart to inhibit RyR2 activity at low luminal [Ca] in planar lipid bilayers. We conclude that the R33Q mutation disrupts interactions of CASQ2 with the RyR2 channel complex and impairs regulation of RyR2 by luminal Ca. These results show that intracellular Ca cycling in normal heart relies on an intricate interplay of CASQ2 with the proteins of the RyR2 channel complex and that disruption of these interactions can lead to cardiac arrhythmia.

Original languageEnglish
Pages (from-to)1151-1158
Number of pages8
JournalCirculation Research
Issue number9
Publication statusPublished - May 2006


  • Ca -induced Ca release
  • Calsequestrin
  • Catecholaminergic polymorphic ventricular tachycardia
  • Ryanodine receptor
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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