Published online before print April 6, 2006, doi: 10.1161/01.RES.0000220647.93982.08
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Submitted on December 20, 2005
Revised on March 14, 2006
Accepted on March 24, 2006
Abnormal Interactions of Calsequestrin With the Ryanodine Receptor Calcium Release Channel Complex Linked to Exercise-Induced Sudden Cardiac Death
Dmitry Terentyev ;
From the Department of Physiology and Cell Biology (D.T., S.V.-K., Z.K., I.G., R.T., S.V., S.G.), Heart and Lung Research Institute, Ohio State University, Columbus; Dipartimento di Scienze Biomediche Sperimentali dell’Università di Padova (A.N., G.V., P.V.), Istituto Interuniversitario di Miologia, Padova, Italy; Department of Molecular Cardiology (M.S., C.N., S.G.P.), Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy; University Hospital Leiden (N.A.B), The Netherlands; Department of Cell Biology and Biochemistry (S.C.W.), Texas Tech University Health Science Center, Lubbock; and Southwest Cancer Center at University Medical Center (S.C.W.), Lubbock, Texas.
* To whom correspondence should be addressed. E-mail: Sandor.Gyorke{at}osumc.edu.
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 CASQ2R33Q 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 (CASQ2WT). As revealed by a Ca indicator trapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the Ca waves occurred at a reduced intra-SR [Ca] accounting for the increased frequency of Ca waves in CASQ2R33Q-expressing myocytes. Recombinant CASQ2WT and CASQ2R33Q 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.
Key words: calsequestrin • ryanodine receptor • sarcoplasmic reticulum • Ca-induced Ca release • catecholaminergic polymorphic ventricular tachycardia
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