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Mutation-linked defective inter-domain interactions within ryanodine receptor as a pathogenic mechanism of catecholaminergic polymorphic ventricular tachycardia

The bulletin of the Yamaguchi Medical School Volume 59 Issue 3-4 Page 25-29
published_at 2012
A050059000301.pdf
[fulltext] 471 KB
Title
Mutation-linked defective inter-domain interactions within ryanodine receptor as a pathogenic mechanism of catecholaminergic polymorphic ventricular tachycardia
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by stress- or exercise- induced ventricular tachycardia, frequently leading to sudden cardiac death. A considerable body of evidence accumulated over recent years suggests that mutation-linked cardiac ryanodine receptor (RyR2) defects cause Ca^2+ leak from sarcoplasmic reticulum, which triggers delayed afterdepolarization and leads to CPVT. However, the underlying mechanism, by which a single mutation in such a large molecule causes drastic effects on the channel function, remains elusive. Here we report that introduction of a human CPVT mutation S2246L into the mouse RyR2 induces aberrant activation of channel gating by forming abnormally tight domain-domain interaction between the S2246L mutable domain and the K201-binding domain. This produces more global conformational change in the RyR2: namely, an aberrant domain unzipping between the N-terminal (a.a. 1–600) domain and the central (a.a. 2000–2500) domain owing to the allosteric conformational coupling mechanism. Pharmacological correction of the defective inter-domain interactions can stop the aberrant Ca^2+ release and lethal arrhythmia. These results provide a new pathogenic mechanism of CPVT and a novel therapeutic strategy against CPVT
Creators Suetomi Takeshi
Creators Yano Masafumi
Creators Matsuzaki Masanori
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Source Identifiers [PISSN] 0513-1812 [NCID] AA00594272
Creator Keywords
ryanodine receptor calcium ventricular tachycardia salcoplasmic reticulum
Resource Type departmental bulletin paper
Publishers Yamaguchi University School of Medicine
Date Issued 2012
File Version Version of Record
Access Rights open access
Schools 大学院医学系研究科(医学)