Cardiac ryanodine receptor function and regulation in heart disease

Stephan E. Lehnart, Xander H.T. Wehrens, Alexander Kushnir, Andrew R. Marks

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

The cardiac ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR) controls intracellular Ca2+ release and muscle contraction in the heart. Ca2+ release via RyR2 is regulated by several physiological mediators. Protein kinase (PKA) phosphorylation dissociates the stabilizing FKBP12.6 subunit (calstabin2) from the RyR2 complex, resulting in increased contractility and cardiac output. Congestive heart failure is associated with elevated plasma catecholamine levels, and chronic stimulation of β-adrenergic receptors leads to PKA hyperphosphorylation of RyR2 in failing hearts. PKA hyperphosphorylation results in calstabin2-depleted RyR2 that displays altered channel gating and may cause aberrant SR Ca2+ release, depletion of SH Ca2+ stores, and reduced myocardial contractility in heart failure. Calstabin2-depleted RyR2 may also trigger cardiac arrhythmias that cause sudden cardiac death. In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), RyR2 missense mutations cause reduced calstabin2 binding to RyR2. Increased RyR2 phosphorylation and pathologically increased calstabin2 dissociation during exercise results in aberrant diastolic calcium release, which may trigger ventricular arrhythmias and sudden cardiac death. In conclusion, heart failure and exercise-induced sudden cardiac death have been linked to defects in RyR2-calstabin2 regulation, and this may represent a novel target for the prevention and treatment of these forms of heart disease.

Original languageEnglish (US)
Pages (from-to)144-159
Number of pages16
JournalAnnals of the New York Academy of Sciences
Volume1015
DOIs
StatePublished - 2004
Externally publishedYes

Keywords

  • Arrhythmia
  • Calcium
  • Calstabin
  • FKBP
  • Heart failure
  • Ryanodine receptor
  • Tachycardia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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