Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?
Thomas Eschenhagen
Thomas Eschenhagen
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4197-4203. https://doi.org/10.1172/JCI45251.
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Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

Abstract

In situations of stress the heart beats faster and stronger. According to Marks and colleagues, this response is, to a large extent, the consequence of facilitated Ca2+ release from intracellular Ca2+ stores via ryanodine receptor 2 (RyR2), thought to be due to catecholamine-induced increases in RyR2 phosphorylation at serine 2808 (S2808). If catecholamine stimulation is sustained (for example, as occurs in heart failure), RyR2 becomes hyperphosphorylated and “leaky,” leading to arrhythmias and other pathology. This “leaky RyR2 hypothesis” is highly controversial. In this issue of the JCI, Marks and colleagues report on two new mouse lines with mutations in S2808 that provide strong evidence supporting their theory. Moreover, the experiments revealed an influence of redox modifications of RyR2 that may account for some discrepancies in the field.

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Thomas Eschenhagen

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Figure 1

The classical view of cardiomyocyte excitation-contraction coupling and its regulation by β-adrenergic receptors.

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The classical view of cardiomyocyte excitation-contraction coupling and ...
Under unstimulated conditions (black arrows), depolarization during an action potential opens LTCCs in T tubules, allowing Ca2+ to enter the cell. This trigger Ca2+ induces a larger Ca2+ release from the SR via RyR2. The increase in Ca2+ concentration initiates conformational changes of the myofilaments and thereby contraction. Removal of Ca2+ via SERCA and NCX reverses the process. Catecholamines stimulate excitation-contraction coupling (red symbols and lettering) by phosphorylating LTCCs (increased Ca2+ influx), PLB (increased Ca2+ reuptake into the SR), and myofilament-based troponin I and myosin-binding protein C (increased relaxation). AC, adenylyl cyclise; Gs, stimulatory G protein. Adapted with permission from Nature (35).