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.

Figure 1. The classical view of cardiomyocyte excitation-contraction coupling and its regulation by β-adrenergic receptors.

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).

Figure 2. The leaky RyR2 hypothesis: phosphorylation and oxidation of RyR2 in the center of a vicious circle in heart failure.

According to Marks and colleagues, catecholamines control excitation-contraction coupling gain not only at the level of LTCCs and PLB, but also at the level of RyR2 by phosphorylating it at S2808. The latter reduces RyR2 affinity for the stabilizing accessory protein, FKBP12.6, and increases its open probability. In heart failure, sustained catecholamine stimulation leads to hyperphosphorylation, leaky RyR2, spontaneous Ca²⁺ release and, via NCX, spontaneous depolarizations. The new data presented in this issue of the JCI (25, 26) now suggest that phosphorylation at S2808 alone does not suffice to dissociate FKBP12.6 but that it needs oxidation of the channel plus phosphorylation. The level of oxidizing ROS is commonly increased in heart failure and, importantly, the increased Ca²⁺ leak from RyR2 (in consequence of oxidation and phosphorylation) further increases ROS production, e.g., from mitochondria. This constitutes a classical vicious circle. Black arrows and lettering indicate basic excitation-contraction coupling; red arrows indicate changes under chronic catecholamine stimulation and heart failure. The red dotted line indicates Ca²⁺ leak. Adapted with permission from Nature (35).