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Publication Abstract from PubMed

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.

Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders.,Miotto MC, Reiken S, Wronska A, Yuan Q, Dridi H, Liu Y, Weninger G, Tchagou C, Marks AR Nat Commun. 2024 Sep 15;15(1):8080. doi: 10.1038/s41467-024-51791-y. PMID:39278969^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.