Regulation of the ryanodine receptor in heart failure

In the heart, calcium (Ca2+) regulates muscle contraction and electrical signals that determine cardiac rhythm and cell growth pathways. The ryanodine receptor (RyR), an intracellular Ca2+ release channel, is required for excitation-contraction coupling. The cardiac RyR has a large cytoplasmic structure that serves as a scaffold for modulatory proteins that regulate the function of the channel. Protein kinase A (PKA) phosphorylation of RyR2 dissociates the regulatory protein FKBP 12.6 and regulates the open probability of the channel. In failing hearts, RyR2 is PKA hyperphosphorylated resulting in defective channel function due to increased sensitivity to Ca2+ induced activation.