scholarly journals Impaired Binding to Junctophilin2 and Nanostructural Alteration in CPVT Mutation

2021 ◽  
Author(s):  
liheng yin ◽  
Alexandra Zahradnikova Jr ◽  
Riccardo Rizzetto ◽  
Simona Boncompani ◽  
Camille Rabesahala de Meritens ◽  
...  
Keyword(s):  
Super Resolution ◽  
Stress Conditions ◽  
Polymorphic Ventricular Tachycardia ◽  
Electronic Microscopy ◽  
Release Channel ◽  
Potential Recording ◽  
Interdomain Interaction ◽  
Ventricular Tachycardias ◽  
Junctional Sarcoplasmic Reticulum ◽  
Impaired Binding

Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca 2+ release channel/ryanodine receptor (RyR2) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal domain, RyR2 R420Q . Objective: To determine the arrhythmogenic mechanisms of this mutation. Methods and Results: Ventricular tachycardias under stress conditions were observed in both CPVT patients and KI mice. During action potential recording (by patch-clamp in KI mouse cardiomyocytes and by microelectrodes in mutant hiPSC-CM) we observed an increased occurrence of delayed after-depolarizations (DADs) under isoproterenol stimulation, associated with increased Ca 2+ waves during confocal Ca 2+ recording in both mouse and human RyR2 R420Q cardiomyocytes. In addition, Ca 2+ -induced Ca 2+ -release, as well as a rough indicator of fractional Ca 2+ release, were higher and Ca 2+ sparks longer in the RyR2 R420Q expressing cells. At the ultrastructural nanodomain level, we observed smaller RyR2 clusters and widened junctional sarcoplasmic reticulum (jSR) measured by g-STED super-resolution and electronic microscopy, respectively. The increase in jSR width might be due to the impairment of RyR2 R420Q binding to junctophilin-2, as there were less junctophilin-2 co-immunoprecipitated with RyR2 R420Q . At the single current level, the RyR2R420Q channel dwells longer in the open state at low [Ca 2+ ] i , but there is predominance of a subconductance state. The latter might be correlated with an enhanced interaction between the N-terminus and the core solenoid, a RyR2 inter-domain association that has not been previously implicated in the pathogenesis of arrhythmias and sudden cardiac death. Conclusions: The RyR2 R420Q CPVT mutation modifies the interdomain interaction of the channel and weaken its association with junctophillin-2. These defects may underlie both nanoscale disarrangement of the dyad and channel dysfunction.

scholarly journals Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Vol 10 (13) ◽  
pp. 2821
Author(s):  
Giulia Borile ◽  
Tania Zaglia ◽  
Stephan E. Lehnart ◽  
Marco Mongillo
Keyword(s):  
Ventricular Tachycardia ◽  
Single Cells ◽  
Tissue Level ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Adrenergic Stimulation ◽  
Release Channel ◽  
Multiphoton Imaging ◽  
Delayed Afterdepolarizations ◽  
Multiple Cells

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.

The Ca2+ release channel in junctional sarcoplasmic reticulum: Gating and blockade by cations

1992 ◽  
Vol 24 (6) ◽  
pp. 903-909 ◽  
Author(s):  
Fernando Soler ◽  
Francisco Fernandez-Belda ◽  
Juan C. Gomez-Fernandez
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Release Channel ◽  
Junctional Sarcoplasmic Reticulum

Ventricular arrhythmias

2019 ◽  
pp. 221-240
Author(s):  
Martin Borggrefe ◽  
Erol Tülümen ◽  
Josep Brugada
Keyword(s):  
Heart Disease ◽  
Ventricular Arrhythmias ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Atrioventricular Node ◽  
Structural Heart Disease ◽  
Polymorphic Ventricular Tachycardia ◽  
European Society Of Cardiology ◽  
Ventricular Tachycardias ◽  
Current Guidelines

Ventricular arrhythmias are abnormal rhythms that originate from below the atrioventricular node. They include premature ventricular complexes, ventricular tachycardias, and ventricular fibrillation. Ventricular arrhythmias may occur in patients with structural heart disease (ischaemic heart disease, cardiomyopathies such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, etc.) or in patients with a structurally normal heart (genetic arrhythmia syndromes such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or as idiopathic ventricular tachycardias). Symptoms depend on the frequency, duration, and haemodynamic effects of the arrhythmia. They may be asymptomatic or may cause symptoms, such as palpitations, shortness of breath, chest discomfort, dizziness, or syncope, or may present with cardiac arrest. This chapter is focused on the role of antiarrhythmic drugs in the management of ventricular arrhythmias. The recommendations are based on the current guidelines of the European Society of Cardiology for the management of patients with ventricular arrhythmias.

scholarly journals Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

2016 ◽  
Vol 473 (21) ◽  
pp. 3951-3964 ◽  
Author(s):  
Xiaowei Zhong ◽  
Bo Sun ◽  
Alexander Vallmitjana ◽  
Tao Mi ◽  
Wenting Guo ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Important Determinant ◽  
Polymorphic Ventricular Tachycardia ◽  
Release Channel ◽  
Cardiac Alternans ◽  
Β Blocker ◽  
Opposite Manner ◽  
Electrocardiogram Ecg

Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+ alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible for cytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+ and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+ alternans in RyR2-SOF hearts, whereas carvedilol, a β-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.

Digestion of cardiac and skeletal muscle junctional sarcoplasmic reticulum vesicles with calpain II. Effects on the Ca2+ release channel.

1990 ◽  
Vol 67 (1) ◽  
pp. 84-96 ◽  
Author(s):  
D P Rardon ◽  
D C Cefali ◽  
R D Mitchell ◽  
S M Seiler ◽  
D R Hathaway ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Release Channel ◽  
Calpain Ii ◽  
Junctional Sarcoplasmic Reticulum

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

2011 ◽  
Vol 301 (4) ◽  
pp. H1625-H1638 ◽  
Author(s):  
Ruey J. Sung ◽  
Chu-Pin Lo ◽  
Pi Yin Hsiao ◽  
Hui-Chun Tien
Keyword(s):  
Ventricular Tachycardia ◽  
Intracellular Calcium ◽  
Markov Models ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Tachyarrhythmias ◽  
Adrenergic Stimulation ◽  
Calcium Cycling ◽  
M Cell ◽  
Release Channel

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of β-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca2+ channel ( ICa,L) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2R4496C+/−) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at ≥0.1 μM could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2R4496C+/− but not in the wild-type via enhancing both ICa,L and sarcoplasmic reticulum (SR) Ca2+ ATPase ( IUP). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient ( D) of ≤0.000766*98 cm2/ms was required for generating DAD-mediated TA in RyR2R4496C+/−. Whereas individual reduction of Ca2+ release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either ICa,L or IUP could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both ICa,L and IUP exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca2+ cycling and a pharmacological regimen capable of reducing ICa,L could be an effective adjunctive to β-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT.

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