The cardiac ryanodine receptor (RyR2) mediates rapid Ca2+ efflux from intracellular stores to effect myocyte contraction during the process of EC (excitation–contraction) coupling. It is now known that mutations in this channel perturb Ca2+ release function, leading to triggered arrhythmias that may cause SCD (sudden cardiac death). Resolving the precise molecular mechanisms by which SCD-linked RyR2 dysfunction occurs currently constitutes a burgeoning area of cardiac research. So far, defective channel phosphorylation, accessory protein binding, luminal/cytosolic Ca2+ sensing, and the disruption of interdomain interactions represent the main candidate mechanisms for explaining aberrant SR (sarcoplasmic reticulum) Ca2+ release via mutants of RyR2. It appears increasingly unlikely that a single exclusive common mechanism underlies every case of mutant channel dysfunction, and that each of these potential mechanisms may contribute to the resultant phenotype. The present review will consider very recent mechanistic developments in this field, including new observations from mutant RyR2 transgenic mouse models, peptide-probe studies, and the implications of functional and phenotypic heterogeneity of RyR2 mutations and polymorphisms.
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November 2007
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Conference Article|
October 25 2007
Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction
N.L. Thomas;
N.L. Thomas
1
1Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, U.K.
1To whom correspondence should be addressed (email thomasnl1@cardiff.ac.uk).
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C.H. George;
C.H. George
1Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, U.K.
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A.J. Williams;
A.J. Williams
1Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, U.K.
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F.A. Lai
F.A. Lai
1Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, U.K.
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Publisher: Portland Press Ltd
Received:
July 20 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (5): 946–951.
Article history
Received:
July 20 2007
Citation
N.L. Thomas, C.H. George, A.J. Williams, F.A. Lai; Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction. Biochem Soc Trans 1 November 2007; 35 (5): 946–951. doi: https://doi.org/10.1042/BST0350946
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