Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca
            <sup>2+</sup>
            Leak Independent of Luminal Ca
            <sup>2+</sup>
            and Trigger Ventricular Arrhythmias in Mice

Chopra, Nagesh; Kannankeril, Prince J.; Yang, Tao; Hlaing, Thinn; Holinstat, Izabela; Ettensohn, Kristen; Pfeifer, Karl; Akin, Brandy L.; Jones, Larry R.; Franzini‐Armstrong, Clara; Knollmann, Björn C.

doi:10.1161/circresaha.107.157552

Cited by 117 publications

(113 citation statements)

References 30 publications

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“…Each molecule of CSQ2 can bind 18 -50 Ca 2ϩ ions. CSQ2 is also believed to regulate the activity of RyR2 Ca 2ϩ release channels by controlling the local luminal Ca 2ϩ concentration in the vicinity of the RyR2 channels (11)(12)(13).…”

Section: Camentioning

confidence: 99%

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Guo

Cala

Song

2012

Journal of Biological Chemistry

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Section: Camentioning

confidence: 99%

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Guo

Cala

Song

2012

Journal of Biological Chemistry

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“…Phospholamban (PLB) inhibits SERCA2a activity, but phosphorylation on either serine 16 (S 16 ) or threonine 17 (T 17 ) relieves this inhibition. Calsequestrin 2 (CSQ2) may be uniquely important for calcium signaling because it is the principal calcium storage protein in the SER and, as part of a protein complex with the ryanodine receptor 2, helps to control the amount of calcium released for contraction (7).…”

mentioning

confidence: 99%

Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice

Sebag

Gillis

Calderone

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Sebag IA, Gillis MA, Calderone A, Kasneci A, Meilleur M, Haddad R, Noiles W, Patel B, Chalifour LE. Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice. Am J Physiol Heart Circ Physiol 301: H1706 -H1715, 2011. First published July 29, 2011; doi:10.1152/ajpheart.00088.2011.-Calcium flux into and out of the sarco(endo)plasmic reticulum is vitally important to cardiac function because the cycle of calcium entry and exit controls contraction and relaxation. Putative estrogen and androgen consensus binding sites near to a CpG island are present in the cardiac calsequestrin 2 (CSQ2) promoter. Cardiomyocytes express sex hormone receptors and respond to sex hormones. We hypothesized that sex hormones control CSQ2 expression in cardiomyocytes and so affect cardiac structure/function. Echocardiographic analysis of male and female C57bl6n mice identified thinner walled and lighter hearts in females and significant concentric remodeling after long-term gonadectomy. CSQ2 and sodium-calcium exchanger-1 (NCX1) expression was significantly increased in female compared with male hearts and decreased postovariectomy. NCX1, but not CSQ2, expression was increased postcastration. CSQ2 expression was reduced when H9c2 cells were cultured in hormone-deficient media; increased when estrogen receptor-␣ (ER␣), estrogen receptor-␤ (ER␤), or androgen agonists were added; and increased in hearts from ER␤-deficient mice. CSQ2 expression was reduced in mice fed a diet low in the methyl donor folic acid and in cells treated with 5-azadeoxycytidine suggesting an involvement of DNA methylation. DNA methylation in CpG in the CSQ2 CpG island was significantly different in males and females and was additionally changed postgonadectomy. Expression of DNA methyltransferases 1, 3a, and 3b was unchanged. These studies strongly link sex hormone-directed changes in CSQ2 expression to DNA methylation with changed expression correlated with altered left ventricular structure and function. protein expression; cardiac function MAINTENANCE OF THE EXPRESSION of calcium homeostasis is important for normal cardiac function (1, 13). Contraction is the consequence of the release of massive amounts of calcium into the cytosol from the sarco(endo)plasmic reticulum (SER) by ryanodine receptor 2. Relaxation is established by the combined action of the sodium-calcium exchanger-1 (NCX1) (30), which removes calcium to the cell exterior, and the sarco(endo)plasmic reticulum ATPase 2a (SERCA2a), which resequesters calcium back to the SER (19). Phospholamban (PLB) inhibits SERCA2a activity, but phosphorylation on either serine 16 (S 16 ) or threonine 17 (T 17 ) relieves this inhibition. Calsequestrin 2 (CSQ2) may be uniquely important for calcium signaling because it is the principal calcium storage protein in the SER and, as part of a protein complex with the ryanodine receptor 2, helps to control the amount of calcium released for contraction (7).The available evide...

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“…CASQ2 null mice, when adrenergically stressed, show enhanced fractional SR Ca 2ϩ release, Ca 2ϩ leak, and arrhythmias (17). Similarly, loss of TRD1 increases susceptibility to triggered arrhythmia (2). These knockout mouse models have shown that the integrity of the triadic protein complex is critical to the proper modulation of RyR2 activity.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background

Kalyanasundaram

Viatchenko‐Karpinski

Belevych

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The role of calsequestrin (CASQ2) in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) transport has gained significant attention since point mutations in CASQ2 were reported to cause ventricular arrhythmia. In the present study, we have critically evaluated the functional consequences of expressing the CASQ2D307H mutant protein in the CASQ2 null mouse. We recently reported that the mutant CASQ2D307H protein can be stably expressed in CASQ2 null hearts, and it targets appropriately to the junctional SR (Kalyanasundaram A, Bal NC, Franzini-Armstrong C, Knollmann BC, Periasamy M. J Biol Chem 285: 3076–3083, 2010). In this study, we found that introduction of CASQ2D307H protein in the CASQ2 null background partially restored triadin 1 levels, which were decreased in the CASQ2 null mice. Despite twofold expression (relative to wild-type CASQ2), the mutant protein failed to increase SR Ca2+ load. We also found that the Ca2+ transient decays slower in the CASQ2 null and CASQ2D307H cells. CASQ2D307H myocytes, when rhythmically paced and challenged with isoproterenol, exhibit spontaneous Ca2+ waves similar to CASQ2 null myocytes; however, the stability of Ca2+ cycling was increased in the CASQ2D307H myocytes. In the presence of isoproterenol, Ca2+-transient amplitude in CASQ2D307H myocytes was significantly decreased, possibly indicating an inherent defect in Ca2+ buffering capacity and release from the mutant CASQ2 at high Ca2+ concentrations. We also observed polymorphic ventricular tachycardia in the CASQ2D307H mice, although lesser than in the CASQ2 null mice. These data suggest that CASQ2D307H point mutation may affect Ca2+ buffering capacity and Ca2+ release. We propose that poor interaction between CASQ2D307H and triadin 1 could affect ryanodine receptor 2 stability, thereby increasing susceptibility to delayed afterdepolarizations and triggered arrhythmic activity.

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Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca ²⁺ Leak Independent of Luminal Ca ²⁺ and Trigger Ventricular Arrhythmias in Mice

Cited by 117 publications

References 30 publications

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice

Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background

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Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca 2+ Leak Independent of Luminal Ca 2+ and Trigger Ventricular Arrhythmias in Mice

Cited by 117 publications

References 30 publications

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Calsequestrin Accumulation in Rough Endoplasmic Reticulum Promotes Perinuclear Ca2+ Release

Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice

Functional consequences of stably expressing a mutant calsequestrin (CASQ2D307H) in the CASQ2 null background

Contact Info

Product

Resources

About

Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca ²⁺ Leak Independent of Luminal Ca ²⁺ and Trigger Ventricular Arrhythmias in Mice

Functional consequences of stably expressing a mutant calsequestrin (CASQ2^D307H) in the CASQ2 null background