Key result
In Casq2-null mice, the RyR2 mutation (E4872Q+/-) prevented stress-induced ventricular tachyarrhythmias, spontaneous Ca2+ waves, and cardiac hypertrophy.
Why the study?
Does the RyR2-resident luminal Ca2+ sensor govern spontaneous Ca2+ waves, ventricular tachyarrhythmias, and cardiac hypertrophy in Casq2-null mice?
Does the RyR2-resident luminal Ca2+ sensor govern spontaneous Ca2+ waves, ventricular tachyarrhythmias, and cardiac hypertrophy in Casq2-null mice?
The RyR2-resident luminal Ca2+ sensor governs spontaneous Ca2+ waves, CPVT, and hypertrophy in Casq2-null mice, making it a potential therapeutic target for Ca2+-mediated arrhythmias.
Answers are grounded in this paper and cite their sources.
Identifies RyR2 luminal Ca2+ sensor as potential antiarrhythmic target; leaves open clinical translation from Casq2-null mouse data.
CASQ2 (cardiac calsequestrin) is commonly believed to serve as the SR (sarcoplasmic reticulum) luminal Ca2+ sensor. Ablation of CASQ2 promotes SCWs (spontaneous Ca2+ waves) and CPVT (catecholaminergic polymorphic ventricular tachycardia) upon stress but not at rest. How SCWs and CPVT are triggered by stress in the absence of the CASQ2-based luminal Ca2+ sensor is an important unresolved question. In the present study, we assessed the role of the newly identified RyR2 (ryanodine receptor 2)-resident luminal Ca2+ sensor in determining SCW propensity, CPVT susceptibility and cardiac hypertrophy in Casq2-KO (knockout) mice. We crossbred Casq2-KO mice with RyR2 mutant (E4872Q+/-) mice, which lack RyR2-resident SR luminal Ca2+ sensing, to generate animals with both deficiencies. Casq2+/- and Casq2-/- mice showed stress-induced VTs (ventricular tachyarrhythmias), whereas Casq2+/-/E4872Q+/- and Casq2-/-/E4872Q+/- mice displayed little or no stress-induced VTs. Confocal Ca2+ imaging revealed that Casq2-/- hearts frequently exhibited SCWs after extracellular Ca2+ elevation or adrenergic stimulation, whereas Casq2-/-/E4872Q+/- hearts had few or no SCWs under the same conditions. Cardiac hypertrophy developed and CPVT susceptibility increased with age in Casq2-/- mice, but not in Casq2-/-/E4872Q+/- mice. However, the amplitudes and dynamics of voltage-induced Ca2+ transients in Casq2-/- and Casq2-/-/E4872Q+/- hearts were not significantly different. Our results indicate that SCWs, CPVT and hypertrophy in Casq2-null cardiac muscle are governed by the RyR2-resident luminal Ca2+ sensor. This implies that defects in CASQ2-based lumi-nal Ca2+ sensing can be overridden by the RyR2-resident luminal Ca2+ sensor. This makes this RyR2-resident sensor a promising molecular target for the treatment of Ca2+-mediated arrhythmias.
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Zhang et al. (2014) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT) and cardiac hypertrophy. RyR2 mutation (E4872Q+/-) vs. Casq2+/- and Casq2-/- mice without the RyR2 mutation was evaluated on Stress-induced ventricular tachyarrhythmias, spontaneous Ca2+ waves, and cardiac hypertrophy. In Casq2-null mice, the RyR2 mutation (E4872Q+/-) prevented stress-induced ventricular tachyarrhythmias, spontaneous Ca2+ waves, and cardiac hypertrophy.
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