PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.
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
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Center for Molecular Cardiology, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Reiken
S
S
Hisamatsu
Y
Y
Jayaraman
T
T
Burkhoff
D
D
Rosemblit
N
N
Marks
A R
AR
D000818:Animals; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D020104:Immunophilins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins
D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D002118:Calcium