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

Marco C. Miotto (), Steven Reiken, Anetta Wronska, Qi Yuan, Haikel Dridi, Yang Liu, Gunnar Weninger, Carl Tchagou and Andrew R. Marks ()
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Marco C. Miotto: Columbia University Vagelos College of Physicians and Surgeons
Steven Reiken: Columbia University Vagelos College of Physicians and Surgeons
Anetta Wronska: Columbia University Vagelos College of Physicians and Surgeons
Qi Yuan: Columbia University Vagelos College of Physicians and Surgeons
Haikel Dridi: Columbia University Vagelos College of Physicians and Surgeons
Yang Liu: Columbia University Vagelos College of Physicians and Surgeons
Gunnar Weninger: Columbia University Vagelos College of Physicians and Surgeons
Carl Tchagou: Columbia University Vagelos College of Physicians and Surgeons
Andrew R. Marks: Columbia University Vagelos College of Physicians and Surgeons

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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 Ca2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca2+ 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 Ca2+ 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.

Date: 2024
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DOI: 10.1038/s41467-024-51791-y

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