Assembling Pieces of the Cardiac Puzzle; Calreticulin and Calcium-Dependent Pathways in Cardiac Development, Health, and Disease

Lynch, Jeffrey M.; Chilibeck, Kaari; Qui, Yuanyuan; Michalak, Marek

doi:10.1016/j.tcm.2006.01.004

Cited by 34 publications

(25 citation statements)

References 35 publications

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“…Furthermore, neither cellular hypertrophy nor t-tubule biogenesis was observed after Ad-CSQ transduction. Developmentally, immature CMs are known to express significant levels of calreticulin; calreticulin decreases after birth due to posttranscriptional modification and is subsequently replaced by CSQ during SR maturation (21,22,31). Our results show that Ad-CSQ transduction also did not affect calreticulin.…”

Section: Discussionmentioning

confidence: 57%

Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Liu¹,

Lieu²,

Siu³

et al. 2009

American Journal of Physiology-Cell Physiology

103

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Section: Discussionmentioning

confidence: 57%

Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Liu¹,

Lieu²,

Siu³

et al. 2009

American Journal of Physiology-Cell Physiology

103

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“…CRT is an important Ca 2+ buffer and regulator of Ca 2+ homeostasis during fetal life (26)(27)(28). CRT is highly expressed in the developing heart, but levels decrease after birth in healthy hearts (29), when CASQ2 assumes its role as the principal SR Ca 2+ -binding protein (7,8). Finding abundant CRT RNA in adult hearts from both WT and CASQ2-deficient mice (Figure 2) strongly suggests that posttranscriptional modification accounts for decreased CRT protein after birth.…”

Section: Tablementioning

confidence: 99%

Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia

Song¹,

Alcalai²,

Arad³

et al. 2007

J. Clin. Invest.

165

175

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Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is a familial disorder caused by cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) gene mutations. To define how CASQ2 mutations cause CPVT, we produced and studied mice carrying a human D307H missense mutation (CASQ 307/307 ) or a CASQ2-null mutation (CASQ ΔE9/ΔE9 ). Both CASQ2 mutations caused identical consequences. Young mutant mice had structurally normal hearts but stress-induced ventricular arrhythmias; aging produced cardiac hypertrophy and reduced contractile function. Mutant myocytes had reduced CASQ2 and increased calreticulin and RyR2 (with normal phosphorylated proportions) but unchanged calstabin levels, as well as reduced total sarcoplasmic reticulum (SR) Ca 2+ , prolonged Ca 2+ release, and delayed Ca 2+ reuptake. Stress further diminished Ca 2+ transients, elevated cytosolic Ca 2+ , and triggered frequent, spontaneous SR Ca 2+ release. Treatment with Mg 2+ , a RyR2 inhibitor, normalized myocyte Ca 2+ cycling and decreased CPVT in mutant mice, indicating RyR2 dysfunction was critical to mutant CASQ2 pathophysiology. We conclude that CPVT-causing CASQ2 missense mutations function as null alleles. In the absence of CASQ2, calreticulin, a fetal Ca 2+ -binding protein normally downregulated at birth, remains a prominent SR component. Adaptive changes to CASQ2 deficiency (increased posttranscriptional expression of calreticulin and RyR2) maintained electrical-mechanical coupling, but increased RyR2 leakiness, a paradoxical response further exacerbated by stress. The central role of RyR2 dysfunction in CASQ2 deficiency unifies the pathophysiologic mechanism underlying CPVT due to RyR2 or CASQ2 mutations and suggests a therapeutic approach for these inherited cardiac arrhythmias. IntroductionCatecholamine-induced polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder characterized by adrenergic-stimulated VT that can deteriorate into ventricular fibrillation to cause sudden cardiac death (1, 2). Recurrent syncope, seizures, and cardiovascular collapse are triggered by exercise or emotional stress (2, 3). Mutations in the cardiac sarcoplasmic reticulum (SR) Ca 2+ release channel, ryanodine receptor type 2 (RyR2), or in cardiac calsequestrin 2 (CASQ2), a SR Ca 2+ -storage protein, cause CPVT (2, 4). Despite considerable knowledge about the coupling of Ca 2+ release from the SR, activation of sarcomere contraction, and Ca 2+ reuptake into the SR during relaxation (reviewed in refs. 5, 6), the mechanisms by which CASQ2 mutations alter Ca 2+ handling or cause CPVT are incompletely understood. CASQ, the most abundant Ca 2+ -buffering protein in the lumen of striated muscle SR (7,8), is encoded by the skeletal (CASQ1) and cardiac (CASQ2) calsequestrin genes (9, 10). Each molecule of CASQ2, a 415-amino acid polypeptide, binds 40-50 Ca 2+ with low affinity (K d = 1 mM), allowing cardiac SR Ca 2+ concentrations to approach 20 mM while free Ca 2+ concentrations are only 1 mM (7,(11)(12)(13). CASQ2 also part...

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“…Calreticulin may regulate the IP 3 R in a Ca 2þ -dependent manner (Camacho and Lechleiter 1995;Naaby-Hansen et al 2001). Furthermore, in a cell culture model, cardiomyocytes derived from crt 2/ -embryonic stem cells showed lower rates of myofibrillar development (Li et al 2002), thought to involve transcriptional pathways regulated by Ca 2þ (Lynch et al 2006). The critical role of Ca 2þ signaling is underscored by the observation that myofibrillar development could be rescued in crt 2/ -cells by transient ionomycin treatment (Li et al 2002).…”

Section: Calreticulin Gain-of-function and Loss-of-functionmentioning

confidence: 99%

Organellar Calcium Buffers

Prins¹,

Michalak²

2011

Cold Spring Harbor Perspectives in Biology

126

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Assembling Pieces of the Cardiac Puzzle; Calreticulin and Calcium-Dependent Pathways in Cardiac Development, Health, and Disease

Cited by 34 publications

References 35 publications

Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia

Organellar Calcium Buffers

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Assembling Pieces of the Cardiac Puzzle; Calreticulin and Calcium-Dependent Pathways in Cardiac Development, Health, and Disease

Cited by 34 publications

References 35 publications

Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia

Organellar Calcium Buffers

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Product

Resources

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Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

Facilitated maturation of Ca²⁺ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression