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Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction

George, Christopher H., Thomas, Nia Lowri ORCID: https://orcid.org/0000-0001-8822-8576, Williams, A. J. and Lai, Francis Anthony ORCID: https://orcid.org/0000-0003-2852-8547 2007. Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction. Biochemical Society Transactions 35 (5) , pp. 946-951. 10.1042/BST0350946

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Portland Press
ISSN: 0300-5127
Last Modified: 27 Oct 2022 10:05
URI: https://orca.cardiff.ac.uk/id/eprint/68881

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