Abstract
The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified the specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation site on recombinant RyR2, distinct from the site for protein kinase A (PKA) that mediates the "fight-or-flight" stress response. CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open probability. CaMKII was activated at increased heart rates, which may contribute to enhanced Ca2+-induced Ca2+ release. Moreover, rate-dependent CaMKII phosphorylation of RyR2 was defective in heart failure. CaMKII-mediated phosphorylation of RyR2 may contribute to the enhanced contractility observed at higher heart rates. The full text of this article is available online at http://circres.ahajournals.org.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic beta-Agonists / pharmacology
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Amino Acid Sequence
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Animals
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Benzylamines / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cardiac Pacing, Artificial
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Enzyme Inhibitors / pharmacology
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Heart Failure / diagnostic imaging
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Heart Failure / etiology
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Heart Failure / metabolism
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Heart Rate / drug effects
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Humans
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Isoproterenol / pharmacology
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Myocardial Infarction / complications
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Myocardium / enzymology*
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Phosphorylation
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Phosphoserine / chemistry
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Protein Processing, Post-Translational*
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Recombinant Fusion Proteins / physiology
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Ryanodine Receptor Calcium Release Channel / chemistry
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Ryanodine Receptor Calcium Release Channel / genetics
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Ryanodine Receptor Calcium Release Channel / physiology*
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Sequence Alignment
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Sequence Homology, Amino Acid
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Sulfonamides / pharmacology
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Tacrolimus Binding Proteins / metabolism
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Ultrasonography
Substances
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Adrenergic beta-Agonists
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Benzylamines
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Enzyme Inhibitors
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Recombinant Fusion Proteins
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Ryanodine Receptor Calcium Release Channel
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Sulfonamides
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KN 93
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Phosphoserine
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Cyclic AMP-Dependent Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Tacrolimus Binding Proteins
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tacrolimus binding protein 1B
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Isoproterenol