Understanding the role of the protein RyR2 in the heart's response to stress

Previous data from Marks' laboratory has indicated that a key part of the response of the heart to prolonged stress is the modification (by phosphorylation on building block serine 2808) of the protein RyR2. In the first of the new reports, Marks and colleagues generated mice in which serine 2808 was replaced with a building block that cannot be phosphorylated and found that their hearts did not beat stronger and faster in response to a chemical substitute for short term stress.

Thus, they conclude that phosphorylation of RyR2 at serine 2808 is important for the short-term response to stress, the fight-or-flight response. In the second paper, they generated mice in which serine 2808 was replaced with a building block that mimics phosphorylated serine. These mice developed heart problems as they aged that could be mitigated with a beta-blocker (the main drugs used to treat heart failure). Thus, Marks and colleagues conclude that one of the mechanisms by which beta-blockers benefit patients with heart failure is by targeting phosphorylated RyR2.

In an accompanying commentary, Thomas Eschenhagen, at the University Medical Center Hamburg Eppendorf, Germany, discusses how the new data generated by Marks and colleagues might help resolve controversies in the field.