PKA phosphorylation of RyR2 dissociates FKBP12.6, and in failing human hearts, RyR2 hyperphosphorylation results in defective channel function due to increased sensitivity to Ca2+-induced activation.
PKA hyperphosphorylation of the RyR2 calcium release channel causes FKBP12.6 dissociation and defective channel function in failing human hearts, providing a molecular mechanism for heart failure pathophysiology.
The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is the major source of calcium (Ca2+) required for cardiac muscle excitation-contraction (EC) coupling. The channel is a tetramer comprised of four type 2 RyR polypeptides (RyR2) and four FK506 binding proteins (FKBP12.6). We show that protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (Po). Using cosedimentation and coimmunoprecipitation we have defined a macromolecular complex comprised of RyR2, FKBP12.6, PKA, the protein phosphatases PP1 and PP2A, and an anchoring protein, mAKAP. In failing human hearts, RyR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to Ca2+-induced activation.
Marx et al. (2000) studied Heart failure. PKA phosphorylation of RyR2 was evaluated on Dissociation of FKBP12.6 and channel open probability. PKA phosphorylation of RyR2 dissociates FKBP12.6, and in failing human hearts, RyR2 hyperphosphorylation results in defective channel function due to increased sensitivity to Ca2+-induced activation.