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Ryanodine receptor mutations and ventricular arrhythmias: channel instability at the heart of Ca2+ release dysfunction

George, Christopher H. 2006. Ryanodine receptor mutations and ventricular arrhythmias: channel instability at the heart of Ca2+ release dysfunction. Journal of Molecular and Cellular Cardiology 40 (6) , p. 985. 10.1016/j.yjmcc.2006.03.191

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Cardiac ryanodine receptors (RyR2) are tetrameric Ca2+ release channels of enormous structural and functional complexity. Inherited or sporadic RyR2 mutations are associated with malignant ventricular arrhythmias induced by exercise or stress, and frequently lead to sudden cardiac death (SCD) in young adolescents. Since 2001, sixty-four mutations have been identified that cluster in three discrete regions of the protein that probably coalesce into close physical proximity in the folded channel architecture. These mutational ‘hot-spots’ in the amino-, central, and carboxyl- terminus are proposed to be critical determinants of intrinsic channel regulation via interdomain interaction. Acquired or mutation-linked weakening of these regional interactions (‘domain unzipping’) is proposed to underlie arrhythmogenesis in heart failure and stress-induced VT, respectively. We used a FRET-based strategy to monitor the dynamic intra-RyR2 interactions that occurred in wild-type and mutant channels in living cells. We showed that clinically severe mutations profoundly disrupted interdomain interactions and caused conformational instability in activated RyR2 channels. Mutation-linked channel instability occurred in diverse cell backgrounds (non-myocytic versus cardiomyocytes), and was independent of the cellular levels of FKBP12.6, a regulatory co-protein whose role in arrhythmia is highly controversial. These new insights provided good evidence for a structural basis of Ca2+ release dysfunction in RyR2-dependent arrhythmia. The implications of these data for the development of novel anti-arrhythmic therapies based on RyR2 stabilisation will be discussed.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 0022-2828
Last Modified: 28 Jun 2019 02:45

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