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Increased Ca2+ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic

María Fernández-Velasco1, Angélica Rueda, Nicoletta Rizzi

  • 1Institut National de la Santé et de la Recherche Médicale, U637, Université de Montpellier, Montpellier, France.

Circulation Research
|December 20, 2008
PubMed

Insights

Mutations in the cardiac ryanodine receptor (RyR2) cause catecholaminergic polymorphic ventricular tachycardia by increasing RyR2

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Cardiac ryanodine receptor (RyR2) mutations are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT).
  • Altered intracellular calcium (Ca2+) handling is implicated in CPVT pathogenesis.

Purpose of the Study:

  • To investigate the Ca2+ handling defect in cardiomyocytes with the RyR2(R4496C) mutation.
  • To elucidate the mechanism by which RyR2 mutations lead to cardiac arrhythmias.

Main Methods:

  • Cardiomyocytes from heterozygous RyR2(R4496C) knock-in mice and wild-type littermates were used.
  • Intracellular Ca2+ ([Ca2+]i) transients were measured using confocal microscopy and fluo-3 fluorescence.
  • Ca2+ release and spark frequency were analyzed under various stimulation rates and beta-adrenergic stimulation.

Main Results:

  • RyR2(R4496C) cardiomyocytes exhibited abnormal diastolic Ca2+ release, manifesting as Ca2+ waves and delayed afterdepolarizations.
  • Increased Ca2+ spark frequency and enhanced Ca2+ sensitivity of RyR2(R4496C) were observed.
  • Beta-adrenergic stimulation increased Ca2+ transient amplitude and spark frequency similarly in both mutant and wild-type cells, indicating unaltered beta-adrenergic sensitivity.

Conclusions:

  • The RyR2(R4496C) mutation increases RyR2 Ca2+ sensitivity, leading to arrhythmogenic diastolic Ca2+ release.
  • This diastolic Ca2+ release lowers the threshold for triggered activity, contributing to CPVT.
  • The study identifies increased Ca2+ sensitivity as the key arrhythmogenic mechanism of the RyR2(R4496C) mutation.

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