Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders

作者：Marco Miotto, Steve Reiken, Anetta Wronska, Qi Yuan, Haikel Dridi, Liu Yang, Gunnar Weninger, Carl Tchagou, Andrew R. Marks · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-51791-y · 被引用次数：35 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Cardiovascular Effects of Exercise

Abstract Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca 2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca 2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca 2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.