Defective calcium (Ca2+) signaling, manifest as a loss of excitation–contraction (EC)
coupling gain in cardiac muscle, likely plays an important role in the pathophysiology of
human heart failure. The mechanism underlying this loss of cardiac EC coupling gain
involves altered regulation of the cardiac ryanodine receptor (RyR2), the major sarcoplasmic
reticulum Ca2+ release channel in the heart. This altered regulation of RyR2 is due, in part,
to hyperphosphorylation of the channel by cyclic adenosine monophosphate-dependent …