Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin.
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Circ. Res. 94 (4): 471--477 (March 2004)

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 (CASQ2(D307H)) on Ca$^2+$ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated approximately 4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2(WT)) or CASQ2(D307H). Expression of CASQ2(D307H) reduced the Ca$^2+$ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic I(Ca)-induced Ca$^2+$ transients and of spontaneous Ca$^2+$ sparks were reduced significantly in myocytes expressing CASQ2(D307H). Myocytes expressing CASQ2(D307H) also displayed drastic disturbances of rhythmic oscillations in Ca$^2+$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 Ca$^2+$ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2(D307H) mutation impairs SR Ca$^2+$ storing and release functions and destabilizes the Ca$^2+$-induced Ca$^2+$ release mechanism by reducing the effective Ca$^2+$ buffering inside the SR and/or by altering the responsiveness of the Ca$^2+$ 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.
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