Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias

Stephan E. Lehnart; Cecile Terrenoire; Steven Reiken; Xander H. T. Wehrens; Long-Sheng Song; Erik J. Tillman; Salvatore Mancarella; James Coromilas; W. J. Lederer; Robert S. Kass; Andrew R. Marks

doi:10.1073/pnas.0602133103

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Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias

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Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias

Stephan E. Lehnart, Cecile Terrenoire, Steven Reiken, Xander H. T. Wehrens, Long-Sheng Song, Erik J. Tillman, Salvatore Mancarella, James Coromilas, W. J. Lederer, Robert S. Kass, …

Proceedings of the National Academy of Sciences - PNAS, Vol.103(20), pp.7906-7910

05/03/2006

DOI: 10.1073/pnas.0602133103

PMCID: PMC1472543

PMID: 16672364

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Abstract

Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the cardiac Ca 2+ release channel/ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutations significantly decrease the binding affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. We have proposed that RyR2-mediated diastolic SR Ca 2+ leak triggers ventricular tachycardia (VT) and sudden cardiac death. In calstabin-2-deficient mice, we have now documented diastolic SR Ca 2+ leak, monophasic action potential alternans, and bidirectional VT. Calstabin-deficient cardiomyocytes exhibited SR Ca 2+ leak-induced aberrant transient inward currents in diastole consistent with delayed after-depolarizations. The 1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 for RyR2, inhibited the diastolic SR Ca 2+ leak, monophasic action potential alternans and triggered arrhythmias. Our data suggest that calstabin-2 deficiency is as a critical mediator of triggers that initiate cardiac arrhythmias.

Biological Sciences

calcium release channel

calstabin

heart failure

JTV519

sudden cardiac death

Details

Title: Subtitle: Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias
Creators: Stephan E. Lehnart - Columbia University
Cecile Terrenoire - †Pharmacology and
Steven Reiken - *Departments of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, and Departments of
Xander H. T. Wehrens - *Departments of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, and Departments of
Long-Sheng Song - Biotechnology Institute
Erik J. Tillman - *Departments of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, and Departments of
Salvatore Mancarella - *Departments of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, and Departments of
James Coromilas - Columbia University
W. J. Lederer - University of Maryland, Baltimore
Robert S. Kass - †Pharmacology and
Andrew R. Marks - Columbia University
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.103(20), pp.7906-7910
DOI: 10.1073/pnas.0602133103
PMID: 16672364
PMCID: PMC1472543
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 05/03/2006
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984293090302771

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