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A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium.

ABSTRACT: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during ?-adrenergic stimulation.This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca(2+)).Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2. RyR2 channels were measured to examine the regulation of the channels by cytosolic versus luminal sarcoplasmic reticulum Ca(2+). A 50-year-old white man with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. cAMP-dependent protein kinase-phosphorylated RyR2-G230C channels exhibited a significantly higher open probability at diastolic Ca(2+) concentrations, associated with a depletion of calstabin2. The luminal Ca(2+) sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like.The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca(2+) dependence for activation under conditions that simulate exercise, consistent with a "leaky" channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca(2+) activation. Thus, diastolic sarcoplasmic reticulum Ca(2+) leak caused by reduced calstabin2 binding and a leftward shift in the Ca(2+) dependence for activation by diastolic levels of cytosolic Ca(2+) is a common mechanism underlying CPVT.

SUBMITTER: Meli AC

PROVIDER: S-EPMC3690513 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium.

Meli Albano C AC Refaat Marwan M MM Dura Miroslav M Reiken Steven S Wronska Anetta A Wojciak Julianne J Carroll Joan J Scheinman Melvin M MM Marks Andrew R AR

Circulation research 20110609 3

<h4>Rationale</h4>Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during β-adrenergic stimulation.<h4>Objective</h4>This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca(2+)).<h4>Methods and results ...[more]

PMID: 21659649

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Project description:BACKGROUND:Long-term aerobic exercise alters autonomic balance, which may not be favorable in heart rate (HR)-dependent arrhythmic diseases including catecholaminergic polymorphic ventricular tachycardia (CPVT) because of preexisting bradycardia and increased sensitivity to parasympathetic stimulation. OBJECTIVE:The purpose of this study was to determine whether long-term exercise-induced autonomic adaptations modify CPVT susceptibility. METHODS:We determined exercise-induced parasympathetic effects on HR, arrhythmia incidence, and intracellular sarcoplasmic reticulum (SR) Ca2+ leak in atrial (ACM) and ventricular (VCM) cardiomyocytes, in exercised (EX) calsequestrin knockout (CASQ2-/-) mice, a model of CPVT. RESULTS:Although 8-week treadmill running improved exercise capacity in EX CPVT mice, the incidence and duration of ventricular tachycardia also increased. HR variability analyses revealed an increased high-frequency component of the power spectrum and root mean square of successive differences in R-R intervals indicating accentuated vagal antagonism during ?-adrenergic stimulation resulting in negligible HR acceleration. In EX CASQ2-/- VCM, peak amplitude of Ca2+ transient (CaT) increased, whereas SR Ca2+ content decreased. Aberrant Ca2+ sparks occurred at baseline, which was exacerbated with isoproterenol. Notably, although 10 ?M of the cholinergic agonist carbachol prevented isoproterenol-induced Ca2+ waves in ACM, CaT amplitude, SR Ca2+ load, and isoproterenol-induced Ca2+ waves paradoxically increased in VCM. In parallel, ventricular ryanodine receptor (RyR2) protein expression increased, whereas protein kinase A- and calmodulin-dependent protein kinase II-mediated phosphorylation of RyR2 was not significantly altered, which could imply an increased number of "leaky" channels. CONCLUSION:Our novel results suggest that long-term exercise in CASQ2-/- mice increases susceptibility to ventricular arrhythmias by accentuating vagal antagonism during ?-adrenergic challenge, which prevents HR acceleration and exacerbates abnormal RyR2 Ca2+ leak in EX CASQ2-/- VCM.

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A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium.

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A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium.

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