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Regular Article

A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium

Albano C. Meli, Marwan M. Refaat, Miroslav Dura, Steven Reiken, Anetta Wronska, Julianne Wojciak, Joan Carroll, Melvin M. Scheinman, Andrew R. Marks
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https://doi.org/10.1161/CIRCRESAHA.111.244970
Circulation Research. 2011;CIRCRESAHA.111.244970
Originally published June 9, 2011
Albano C. Meli
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Marwan M. Refaat
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Miroslav Dura
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Steven Reiken
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Anetta Wronska
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Julianne Wojciak
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Joan Carroll
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Melvin M. Scheinman
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Andrew R. Marks
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Abstract

Rationale: 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.

Objective: This study sought to determine the effects of a novel identified RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca2+).

Methods: 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 Ca2+.

Results: 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 Ca2+ concentrations, associated with a depletion of calstabin2. The luminal Ca2+ sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like.

Conclusions: 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 Ca2+ dependence for activation under conditions that simulate exercise, consistent with a “leaky” channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca2+ activation. Thus, diastolic sarcoplasmic reticulum Ca2+ leak caused by reduced calstabin2 binding and a leftward shift in the Ca2+ dependence for activation by diastolic levels of cytosolic Ca2+ is a common mechanism underlying CPVT.

  • CPVT
  • sudden cardiac death
  • ryanodine receptor
  • calstabin
  • Received March 16, 2011.
  • Revision received May 24, 2011.
  • Accepted May 26, 2011.
  • © 2011 American Heart Association, Inc.
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    A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium
    Albano C. Meli, Marwan M. Refaat, Miroslav Dura, Steven Reiken, Anetta Wronska, Julianne Wojciak, Joan Carroll, Melvin M. Scheinman and Andrew R. Marks
    Circulation Research. 2011;CIRCRESAHA.111.244970, originally published June 9, 2011
    https://doi.org/10.1161/CIRCRESAHA.111.244970

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    A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium
    Albano C. Meli, Marwan M. Refaat, Miroslav Dura, Steven Reiken, Anetta Wronska, Julianne Wojciak, Joan Carroll, Melvin M. Scheinman and Andrew R. Marks
    Circulation Research. 2011;CIRCRESAHA.111.244970, originally published June 9, 2011
    https://doi.org/10.1161/CIRCRESAHA.111.244970
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