Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease

Abstract

Cardiac ryanodine receptor type 2 plays a key role in excitation-contraction coupling. The ryanodine receptor type 2 channel protein is modulated by various post-translational modifications, including phosphorylation by protein kinase A and Ca(2+)/calmodulin protein kinase II. Despite extensive research in this area, the functional effects of ryanodine receptor type 2 phosphorylation remain disputed. In particular, the potential involvement of increased ryanodine receptor type 2 phosphorylation in the pathogenesis of heart failure and arrhythmias remains a controversial area, which is discussed in this review article.

Keywords: atrial fibrillation; heart failure; phosphorylation; ryanodine receptor type 2.

Figure 1

Number of peer-reviewed papers published between 1988–2013, containing key words ‘ryanodine receptors’ and ‘phosphorylation’ in key bibliographic fields, according to Scopus.

Figure 2

Schematic representation of the key determinants of excitation-contraction coupling in cardiomyocytes. Physiologicallly, Ca²⁺-entry through L-type Ca²⁺-channels (I_Ca,L) triggers SR Ca²⁺-release through RyR2. The systolic Ca²⁺-transient activates myofilaments, initiating contraction. Diastolic relaxation occurs when Ca²⁺ is transported into SR via SERCA2a and out of the myocyte via NCX1. In heart failure (HF) and atrial fibrillation (AF), altered RyR2-phosphorylation increases SR Ca²⁺-leak, promotes Ca²⁺-dependent remodeling and impairs contractility. Spontaneous SR Ca²⁺-release events (SCaEs) promote delayed afterdepolarizations (DADs) and triggered activity. Inset shows RyR2-macromolecular complex with accessory proteins, protein kinases and phosphatases (and their respective anchoring proteins) that control phosphorylation levels. Protein kinase-A (PKA) and Ca²⁺-calmodulin-dependent protein kinase-II (CaMKII)-dependent phosphorylation sites are indicated with blue and green “P” symbols, respectively.