PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts
PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts
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DOI：
10.1016/s0092-8674(00)80847-8
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发表时间：
2000-05-12
期刊：
影响因子：
64.5
通讯作者：
Marks, AR
中科院分区：
文献类型：
--
作者：
Marx, SO;Reiken, S;Marks, AR
肌浆网（SR）上的Ryanodine受体（RyR）/钙释放通道是心肌兴奋-收缩（EC）偶联所需钙（Ca 2+）的主要来源。该通道是由四种2型RyR多肽（RyR 2）和四种FK 506结合蛋白（FKBP 12.6）组成的四聚体。我们发现RyR 2的蛋白激酶A（PKA）磷酸化使FKBP12.6解离并调节通道开放概率（P-o）。使用共沉淀和免疫共沉淀，我们已经定义了一个大分子复合物的RyR 2，FKBP 12.6，PKA，蛋白磷酸酶PP 1和PP 2A，和锚定蛋白，mAKAP。在衰竭的人类心脏中，RyR 2被PKA过度磷酸化，由于对Ca 2+诱导的激活的敏感性增加而导致通道功能缺陷。
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 (P-o). 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.