Pathogenic mechanism of a catecholaminergic polymorphic ventricular tachycardia causing-mutation in cardiac calcium release channel RyR2

Journal of Molecular and Cellular Cardiology
Jing XiongZheng Liu

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition that is characterized by an abnormal heart rhythm in response to physical or emotional stress. The majority CPVT patients carry mutations in the RYR2 gene that encodes the calcium release channel/ryanodine receptor (RyR2) in cardiomyocytes. The pathogenic mechanisms that account for the clinical phenotypes of CPVT are still elusive. We have identified a de novo mutation, A165D, from a CPVT patient. We found that CPVT phenotypes are recapitulated in A165D knock-in mice. The mutant RyR2 channels enhanced sarcoplasmic reticulum Ca2+ release, triggered delayed afterdepolarization in cardiomyocytes. Structural analysis revealed that the A165D mutation is located in a loop that is involved in inter-subunit interactions in the RyR2 tetrameric structure, it disrupted conformational stability of the RyR2, which favored a closed-to-open state transition, resulting in a leaky channel. The loop also harbors several other CPVT mutations, which suggests a common pathogenic molecular mechanism of CPVT-causing mutations. Our data illustrated disease-relevant functional defects and provide a deeper mechanistic understanding of a life-threatening cardiac arrhythmia.

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Citations

Aug 24, 2019·Journal of Molecular Neuroscience : MN·Qu ChenQiujian Zhao
Dec 17, 2019·The Journal of General Physiology·Toshiko YamazawaMasamitsu Iino
Feb 11, 2020·Journal of Muscle Research and Cell Motility·Haruo OgawaTakashi Murayama
Sep 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vladena Bauerová-HlinkováJacob A Bauer

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