Ca 2+ -dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca 2+ cycling refers to the release and reuptake of intracellular Ca 2+ that drives muscle contraction and relaxation. In failing hearts, Ca 2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca 2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca 2+ storage organelle in muscle. Defects in the regulation of Ca 2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/ Ca 2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in "leaky" channels in failing hearts. These leaky RyR2s contribute to depletion of Ca 2+ from the SR, and the leaking Ca 2+ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca 2+ reuptake that conspires with leaky RyR2 to deplete SR Ca 2+ . Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca 2+ -release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca 2+ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca 2+ cycling in the heart.
Excitation-contraction couplingWith each beat of the heart, Ca 2+ is released from the sarcoplasmic reticulum (SR) via the ryanodine receptor 2, cardiac (RyR2), raising the cytosolic Ca 2+ concentration about ten-fold (∼1 μM) and activating cardiac muscle contraction (Figure 1). The Ca 2+ is then pumped back into the SR by the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a), lowering the cytosolic Ca 2+ concentration to baseline levels (∼100 nM) and causing relaxation. The Ca 2+ release and reuptake cycle is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and the specialized invagination called the transverse tubule (T tubule). Voltage-gated Ca 2+ channels on the T tubule are activated by depolarization and allow a small amount of Ca 2+ to run down its concentration gradient from mM external Ca 2+ concentration to nM internal Ca 2+ concentration. This entering Ca 2+ binds to and activates RyR2 channels, which release Ca 2+ stored at high concentration (in the millimolar range) in the SR. The Ca 2+ binds to troponin C, allowing actin-myosin cross-bridging and the thick and thin filaments of the sarcomere to slide past each other, shortening the sarcomere and causing cardiac muscle contraction.
Heart failureHeart failure (HF) is the leading cause of mortality and morbidity in developed countries. The incidence of HF continues to increase a...