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Circulation Research. 2004;94:471-477
Published online before print January 8, 2004, doi: 10.1161/01.RES.0000115944.10681.EB
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(Circulation Research. 2004;94:471.)
© 2004 American Heart Association, Inc.

Cellular Biology

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

From the Departments of Physiology (S.V.-K., D.T., I.G., R.T., S.G.) and Cell Biology and Biochemistry (S.C.W.), Texas Tech University Health Sciences Center, and Southwest Cancer Center at University Medical Center (S.C.W.), Lubbock, Tex; Dipartimento di Scienze Biomediche Sperimentali dell’Universita degli Studi di Padova (P.V., A.N.), Padova, Italy; and Department of Molecular Cardiology (S.G.P., C.N.), Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy.

Correspondence to Sandor Gyorke, Department of Physiology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430-6551. E-mail sandor.gyorke{at}ttuhsc.edu

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 {approx}4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2WT) 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 Ca2+ 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 Ca2+-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 Ca2+. 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.


Key Words: excitation-contraction coupling • calcium-induced calcium release • catecholaminergic polymorphic ventricular tachycardia • sarcoplasmic reticulum • calsequestrin




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