Marx S O, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks A R
Center for Molecular Cardiology, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Cell. 2000 May 12;101(4):365-76. doi: 10.1016/s0092-8674(00)80847-8.
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.
肌浆网（SR）上的兰尼碱受体（RyR）/钙释放通道是心肌兴奋 - 收缩（EC）偶联所需钙（Ca2 +）的主要来源。该通道是一种四聚体，由四个2型RyR多肽（RyR2）和四个FK506结合蛋白（FKBP12.6）组成。我们发现RyR2的蛋白激酶A（PKA）磷酸化会使FKBP12.6解离并调节通道开放概率（Po）。通过共沉降和共免疫沉淀，我们确定了一个由RyR2、FKBP12.6、PKA、蛋白磷酸酶PP1和PP2A以及锚定蛋白mAKAP组成的大分子复合物。在衰竭的人类心脏中，RyR2被PKA过度磷酸化，由于对Ca2 +诱导激活的敏感性增加而导致通道功能缺陷。
