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

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

SUBMITTER: Miotto MC 

PROVIDER: S-EPMC11402997 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature