The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice.
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.
*Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A.
Jingqun
J
Zhang
†Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A.
Biyi
B
Chen
‡Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1.
Xiaowei
X
Zhong
‡Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1.
Tao
T
Mi
†Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A.
Ang
A
Guo
*Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A.
Qiang
Q
Zhou
*Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A.
Zhen
Z
Tan
*Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A.
Guogen
G
Wu
‡Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1.
Alexander W
AW
Chen
*Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A.
Michael
M
Fill
†Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A.
Long-Sheng
LS
Song
S R Wayne
SR
Chen
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002155:Calsequestrin / Q000172:deficiency* / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium