Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain

Handhle, Ahmed; Ormonde, Chloe E.; Thomas, N. Lowri; Bralesford, Catherine; Williams, Alan J.; Lai, F. Anthony; Zissimopoulos, Spyros

doi:10.1242/jcs.191643

Cited by 17 publications

(12 citation statements)

References 33 publications

(50 reference statements)

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“…A reduction of CASQ2 and a consequent reduction of Ca 2+ binding capacity facilitates Ca 2+ -release and increases the event frequency. 51 At lower level of CASQ2, the SR Ca 2+ load threshold at which spontaneous Ca 2+ release happens is lower, increasing the overall probability of arrhythmias. 52 The efficacy of JTV-519 to terminate tachycardia in 46% of EHTs support the hypothesis that altered intracellular Ca 2+ handling participates in these tachycardia episodes.…”

Section: Discussionmentioning

confidence: 99%

Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue

Lemme

Braren

Prondzynski

et al. 2019

Cardiovascular Research

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Aims Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs). Methods and results To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15 s bursts of blue light pulses (0.3 mW/mm2, 30 ms, 3 Hz) separated by 15 s without pacing for 3 weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 µmol/L) to terminate tachycardia indicate alterations of Ca2+ handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 µmol/L) and E-4031 (100% at 1 µmol/L) were also effective, but not ivabradine (1 µmol/L) or SEA0400 (10 µmol/L). Conclusion We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia.

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Section: Discussionmentioning

confidence: 99%

Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue

Lemme

Braren

Prondzynski

et al. 2019

Cardiovascular Research

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“…This function is effective through protein-protein interactions, with junctin and triadin (Zhang et al, 1997;Shin et al, 2000). However, a direct interaction between CASQ2 and RyR2 has recently been described (Handhle et al, 2016). Junctin is a 26 kDa transmembrane protein forming a complex with triadin, CASQ2, and RyR2.…”

Section: The Ryr2 Complexmentioning

confidence: 99%

Unbalance Between Sarcoplasmic Reticulum Ca2 + Uptake and Release: A First Step Toward Ca2 + Triggered Arrhythmias and Cardiac Damage

et al. 2020

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The present review focusses on the regulation and interplay of cardiac SR Ca 2+ handling proteins involved in SR Ca 2+ uptake and release, i.e., SERCa2/PLN and RyR2. Both RyR2 and SERCA2a/PLN are highly regulated by post-translational modifications and/or different partners' proteins. These control mechanisms guarantee a precise equilibrium between SR Ca 2+ reuptake and release. The review then discusses how disruption of this balance alters SR Ca 2+ handling and may constitute a first step toward cardiac damage and malignant arrhythmias. In the last part of the review, this concept is exemplified in different cardiac diseases, like prediabetic and diabetic cardiomyopathy, digitalis intoxication and ischemia-reperfusion injury.

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“…CASQ2 may exert important modulatory inhibitory or enhancing effects on RyR2‐mediated Ca 2+ release at low or high SR luminal Ca 2+ concentrations, respectively 55–57 . This may complement the modulation arising from the sensing of luminal Ca 2+ by the RyR2 itself 31,58 .…”

Section: Resultsmentioning

confidence: 99%

Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex

Saadeh

Achercouk

Fazmin

et al. 2020

Annals of the New York Academy of Sciences

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with mutations in the cardiac ryanodine receptor (RyR2). These result in stress-induced ventricular arrhythmic episodes, with clinical symptoms and prognosis reported more severe in male than female patients. Murine homozygotic RyR2-P2328S (RyR2 S/S) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca 2+ leak and disrupted Ca 2+ homeostasis. In addition, RyR2 S/S hearts show decreased myocardial action potential conduction velocities (CV), all features implicated in arrhythmic trigger and substrate. The present studies explored for independent and interacting effects of RyR2 S/S genotype and sex on expression levels of molecular determinants of Ca 2+ homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and Ca V 1.2) and CV (Na V 1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-β1) in mice. Expression levels of Ca 2+ homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca 2+ homeostasis. Furthermore, altered Na V 1.5, phosphorylated Cx43, and TGF-β1 expression were not implicated in the development of slowed CV. By contrast, decreased Cx43 expression correlated with slowed CV, in female, but not male, RyR2 S/S mice. The CV changes may reflect acute actions of the increased cytosolic Ca 2+ on Na V 1.5 and Cx43 function.

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Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain

Cited by 17 publications

References 33 publications

Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue

Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue

Unbalance Between Sarcoplasmic Reticulum Ca2 + Uptake and Release: A First Step Toward Ca2 + Triggered Arrhythmias and Cardiac Damage

Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex

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