Cardiac ryanodine receptor phosphorylation: target sites and functional consequences

Abstract

A study by Xiao and co-workers in this issue of the Biochemical Journal demonstrates PKA (protein kinase A)-dependent phosphorylation of Ser-2030 on the cardiac ryanodine receptor (RyR2) that is activated by β-adrenergic agonists. They show that RyR2 phosphorylation at this site is not appreciably altered in heart failure samples, but retains PKA-dependence of phosphorylation. They contrast this with RyR2 phosphorylation at Ser-2808, a site previously reported to be the key and only PKA target site on RyR2. Here Ser-2808 phosphorylation was found to be relatively insensitive to either PKA activation or inhibition. These results add important new information to a highly controversial field. This issue is important because it is increasingly clear that altered regulation of the gating of the RyR2 sarcoplasmic reticulum Ca 2+ -release channel (e.g. by phosphorylation) is critically important in mediating altered diastolic sarcoplasmic reticulum Ca 2+ release. This may contribute to both reduced cardiac function and arrhythmogenesis in humans carrying mutations in the RyR2 gene and with acquired heart failure of varied aetiology. This study brings some new answers, but also raises additional new questions that will require further investigation.

Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes

“…A similar preservation of ss CaTs was found in an ovine AF (12) and a canine RAP model (13), albeit with lesser reductions in I Ca,L . Ca 2+ sensitization due to RyR2 hyperphosphorylation could contribute to facilitated SR Ca 2+ release in the ss domain (44). In line with this hypothesis, our simulations indicated an increased Ca 2+ sensitivity of RyR2 after RAP.…”

Inherited Arrhythmias

“…109 -111 Additionally, changes in the Ca 2ϩ sensitivity of excitation-contraction coupling and Ca 2ϩ cycling proteins can directly contribute to arrhythmogenesis. 107,112,113 Under …”

The mAKAP signalosome and cardiac myocyte hypertrophy

“…However, despite their extensive investigations, their model has been disputed. The controversy surrounding RyR2 regulation has been discussed in detail in recent reviews (38,39). Regardless, it is not clear how germane the Marks model is to the regulation of mAKAPb-associated RyR2.…”