Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure

Abstract

The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca(2+) release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca(2+) release in heart failure.

Dantrolene prevents arrhythmogenic Ca2+release in heart failure

“…Furthermore, dantrolene binds to the corresponding sequence (amino acids 601-620) of RyR2 (33,47) and has recently been proposed to have effects on cardiac RyR2 (24,50); however, no effect of the drug on the properties of native RyR2 channels has been observed in single channel analysis (12). Recent evidence has suggested that dantrolene may ameliorate abnormal RyR2-mediated Ca 2ϩ release associated with heart failure (HF) (24,31). In HF (7), it has been hypothesized that interdomain interactions between the NH 2 -terminal and central domains of the RyR2 channel become destabilized or unzipped [possibly through posttranslational modifications such as phosphorylation (1,30) or oxidation (44)], thus contributing to channel dysfunction and altering cellular Ca 2ϩ -handling properties.…”

“…The loss of Ca 2ϩ from the cell decreases SR Ca 2ϩ content and subsequently weakens myocyte contraction as less Ca 2ϩ is available for beat-to-beat activation of the contractile proteins (26,35). Recent investigations have suggested that dantrolene may correct the abnormal RyR2-mediated Ca 2ϩ release associated with HF by stabilizing the interdomain interactions of RyR2 and preventing diastolic SR Ca 2ϩ release (23,24,31).…”

Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes

“…Recently, we found that domain unzipping seen in failing hearts also dissociates CaM as in the case of CPVT, and rebinding of CaM ameliorates the stability of the RyR2 [10,20]. These findings indicate that dissociation of CaM allosterically linked to domain unzipping plays a critical role in abnormal Ca 2+ handling as a common pathogenic mechanism underlying CPVT and heart failure, by which aberrant Ca 2+ release is induced.…”

“…In our previous study, we showed that CaM binding affinity of RyR is markedly decreased, thereby inducing spontaneous Ca 2+ leak which leads to contractile dysfunction and arrhythmia [9,10,20]. Moreover, in failing hearts we found that CaM-(Gly-Ser-His), which shows higher binding affinity to the RyR1 than CaM [21], stabilized the RyR2 channel, inhibited Ca 2+ leak, and improved myocyte function [10].…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…Whereas unzipping of N-terminal and central domains was associated with spontaneous SR Ca 2+ leak, dantrolene suppressed both unzipping and SR Ca 2+ leak (sparks) and ultimately delayed afterdepolarizations, which are common in heart failure. Additionally, dantrolene restores calmodulin (CaM) binding to RyR2, which is usually attenuated in heart failure [39] .…”