Circulation Research. 2004;94:e61-e70
Published online before print March 11, 2004, doi: 10.1161/01.RES.0000125626.33738.E2
Published online before print March 11, 2004, doi: 10.1161/01.RES.0000125626.33738.E2
© 2004 American Heart Association, Inc.
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Ca2+/Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor
From the Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Andrew R. Marks, MD, Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 W 168th St, P&S 9-401, Box 65, New York, NY 10032. E-mail arm42{at}columbia.edu
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.
Key Words: ryanodine receptor • calcium • Ca2+/calmodulin-dependent kinase II • protein kinase A • heart failure
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