Sarcoplasmic reticulum calcium leak and cardiac arrhythmias

Biochem Soc Trans. 2007 Nov;35(Pt 5):952-6. doi: 10.1042/BST0350952.


Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca(2+)) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca(2+) leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca(2+) leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca(2+) leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca(2+) leak through SR Ca(2+) release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Arrhythmias, Cardiac / metabolism*
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Humans
  • Mutation
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum / metabolism*
  • Tacrolimus Binding Proteins / metabolism


  • Ryanodine Receptor Calcium Release Channel
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 1B
  • Calcium