The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice

Jingqun Zhang; Biyi Chen; Xiaowei Zhong; Tao Mi; Ang Guo; Qiang Zhou; Zhen Tan; Guogen Wu; Alexander W Chen; Michael Fill; Long-Sheng Song; S R Wayne Chen

doi:10.1042/BJ20140126

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The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice

Journal article

Peer reviewed

The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice

Jingqun Zhang, Biyi Chen, Xiaowei Zhong, Tao Mi, Ang Guo, Qiang Zhou, Zhen Tan, Guogen Wu, Alexander W Chen, Michael Fill, …

The Biochemical journal, Vol.461(1), pp.99-106

07/01/2014

DOI: 10.1042/BJ20140126

PMCID: PMC4277184

PMID: 24758151

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https://www.ncbi.nlm.nih.gov/pmc/articles/4277184View

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Abstract

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.

Animals

Calcium - metabolism

Calcium Signaling - physiology

Calsequestrin - deficiency

Calsequestrin - genetics

Cardiomegaly - genetics

Cardiomegaly - metabolism

Cardiomegaly - physiopathology

Mice

Mice, Knockout

Mutation - genetics

Ryanodine Receptor Calcium Release Channel - genetics

Ryanodine Receptor Calcium Release Channel - physiology

Tachycardia, Ventricular - genetics

Tachycardia, Ventricular - metabolism

Tachycardia, Ventricular - physiopathology

Details

Title: Subtitle: The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice
Creators: Jingqun Zhang - Rush University Medical Center
Biyi Chen - University of Iowa
Xiaowei Zhong - Libin Cardiovascular Institute of Alberta
Tao Mi - Libin Cardiovascular Institute of Alberta
Ang Guo - University of Iowa
Qiang Zhou - Rush University Medical Center
Zhen Tan - Rush University Medical Center
Guogen Wu - Rush University Medical Center
Alexander W Chen - University of Calgary
Michael Fill - Rush University Medical Center
Long-Sheng Song - University of Iowa
S R Wayne Chen - Libin Cardiovascular Institute of Alberta
Resource Type: Journal article
Publication Details: The Biochemical journal, Vol.461(1), pp.99-106
DOI: 10.1042/BJ20140126
PMID: 24758151
PMCID: PMC4277184
NLM abbreviation: Biochem J
ISSN: 0264-6021
eISSN: 1470-8728
Grant note: R01HL090905 / NHLBI NIH HHS R01 HL057832 / NHLBI NIH HHS R01 HL075210 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS R01HL057832 / NHLBI NIH HHS R01HL75210 / NHLBI NIH HHS
Language: English
Date published: 07/01/2014
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984293087102771

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