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

Nat Commun. 2024 Sep 15;15(1):8080. doi: 10.1038/s41467-024-51791-y.

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.

MeSH terms

  • Animals
  • Arrhythmias, Cardiac* / genetics
  • Arrhythmias, Cardiac* / metabolism
  • Calcium* / metabolism
  • Cryoelectron Microscopy*
  • Death, Sudden, Cardiac / etiology
  • Heart Failure* / genetics
  • Heart Failure* / metabolism
  • Humans
  • Mutation
  • Ryanodine Receptor Calcium Release Channel* / chemistry
  • Ryanodine Receptor Calcium Release Channel* / genetics
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • Sarcoplasmic Reticulum / metabolism

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Calcium
  • RyR2 protein, human