Ryanodine receptors, FKBP12, and heart failure.
RyR2 function is regulated by highly conserved signaling pathways that modulate excitation-contraction (EC) coupling. cAMP dependent protein kinase (PKA) phosphorylation of RyR2 plays an important role in regulating channel function in response to stress signaled by the sympathetic nervous system (the classic "fight or flight response") (1). PKA phosphorylation of RyR2 induces dissociation of the regulatory protein FKBP12.6 resulting in channels with increased sensitivity to Ca2+-induced Ca2+ release. Under normal physiological conditions (no cardiac damage) PKA phosphorylation of RyR2 is part of an integrated physiological response that leads to increased EC coupling gain and increased cardiac output. PKA-hyperphosphorylation of RyR2 in failing hearts is a maladaptive response that results in depletion of FKBP12.6 from the RyR2 macromolecular complex and defective channel function (pathologically increased sensitivity to Ca2+-induced Ca2+ release) that may cause depletion of SR Ca2+ and diastolic release of SR Ca2+ that can initiate delayed after depolarizations (DADs) that trigger ventricular arrhythmias (1). RyR2 mutations in patients with catecholaminergic induced sudden cardiac death provide further evidence linking the sympathetic nervous system, RyR2 and ventricular arrhythmias (2-4). The chronic hyperadrenergic state of heart failure is associated with defective Ca2+ signaling in part due to PKA hyperphosphorylation of RyR2.
Marks
Andrew R
AR
Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. arm42@columbia.edu
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D020013:Calcium Signaling; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D008955:Models, Cardiovascular; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D022061:Tacrolimus Binding Protein 1A