Orphaned ryanodine receptors in the failing heart

Long Sheng Song, Eric A. Sobie, Stacey McCulle, W. J. Lederer, C. William Balke, Heping Cheng

Research output: Contribution to journalArticlepeer-review

364 Scopus citations


Heart muscle is characterized by a regular array of proteins and structures that form a repeating functional unit identified as the sarcomere. This regular structure enables tight coupling between electrical activity and Ca 2+ signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca2+ signaling, and arrhythmias; however, the underlying causes of these defects are not well understood. Here, in ventricular myocytes from spontaneously hypertensive rats that develop heart failure, we identify fundamental changes in Ca2+ signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca2+ release and increased spatial dispersion of the transverse tubules (TTs). Remodeled TTs in cells from failing hearts no longer exist in the regularly organized structures found in normal heart cells, instead moving within the sarcomere away from the Z-line structures and leaving behind the sarcoplasmic reticulum Ca2+ release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca2+ sparks that have been linked to blunted contractility and, probably, Ca2+-dependent arrhythmias in diverse models of heart failure. We conclude that the increased spatial dispersion of the TTs and orphaned RyRs lead to the loss of local control and Ca2+ instability in heart failure.

Original languageEnglish
Pages (from-to)4305-4310
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 14 2006


  • Calcium signaling
  • Dyssynchrony
  • Heart failure
  • Local control
  • Transverse tubules


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