Ryanodine receptors/calcium release channels in heart failure and sudden cardiac death.
Calcium (Ca2+) ions are second messengers in signaling pathways in all types of cells. They regulate muscle contraction, electrical signals which determine the cardiac rhythm and cell growth pathways in the heart. In the past decade cDNA cloning has provided clues as to the molecular structure of the intracellular Ca2+ release channels (ryanodine receptors, RyR, and inositol 1,4,5-trisphosphate receptors, IP3R) on the sarcoplasmic and endoplasmic reticulum (SR/ER) and an understanding of how these molecules regulate Ca2+ homeostasis in the heart is beginning to emerge. The intracellular Ca2+ release channels form a distinct class of ion channels distinguished by their structure, size, and function. Both RyRs and IP3Rs have gigantic cytoplasmic domains that serve as scaffolds for modulatory proteins that regulate the channel pore located in the carboxy terminal 10% of the channel sequence. The channels are tetramers comprised of four RyR or IP3R subunits. RyR2 is required for excitation-contraction (EC) coupling in the heart. Using co-sedimentation and co-immunoprecipitation we have defined a macromolecular complex comprised of RyR2, FKBP12.6, PKA, the protein phosphatases PP1 and PP2A, and an anchoring protein mAKAP. We have shown that protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (P(o)). In failing human hearts RyR2 is PKA hyperphosphorylated resulting in defective channel function due to increased sensitivity to Ca2+-induced activation.
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Center for Molecular Cardiology, Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. arm42@columbia.edu
D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004594:Electrophysiology; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism / Q000502:physiology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism / Q000502:physiology
D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B