Cryo-EM structures reveal that heart failure and CPVT-linked RyR2 variants adopt a pathological primed state causing calcium leak, which is reversed towards the closed state by the Rycal drug ARM210.
Identifies the 'primed' state of the RyR2 channel as a unifying structural mechanism for calcium leak in heart failure and arrhythmias, which can be targeted therapeutically by Rycal drugs.
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.
Miotto et al. (Sun,) conducted a other in Heart failure and arrhythmogenic disorders (CPVT). Rycal drug ARM210 vs. Untreated mutant RyR2 channels was evaluated on Structural conformation (RMSD) and calstabin-2 binding affinity. Cryo-EM structures reveal that heart failure and CPVT-linked RyR2 variants adopt a pathological primed state causing calcium leak, which is reversed towards the closed state by the Rycal drug ARM210.