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(Circulation Research. 2006;99:398.)
© 2006 American Heart Association, Inc.

Cellular Biology

Ca²⁺/Calmodulin-Dependent Protein Kinase II Phosphorylation of Ryanodine Receptor Does Affect Calcium Sparks in Mouse Ventricular Myocytes

Tao Guo, Tong Zhang, Ruben Mestril, Donald M. Bers

From the Department of Physiology and Cardiovascular Institute (T.G., R.M., D.M.B.), Loyola University Chicago, Stritch School of Medicine, Maywood, IL; and the Department of Pharmacology (T.Z.), University of California–San Diego.

Correspondence to Donald M. Bers, PhD, Dept of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Previous studies in transgenic mice and with isolated ryanodine receptors (RyR) have indicated that Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) can phosphorylate RyR and activate local diastolic sarcoplasmic reticulum (SR) Ca²⁺ release events (Ca²⁺ sparks) and RyR channel opening. Here we use relatively controlled physiological conditions in saponin-permeabilized wild type (WT) and phospholamban knockout (PLB-KO) mouse ventricular myocytes to test whether exogenous preactivated CaMKII or endogenous CaMKII can enhance resting Ca²⁺ sparks. PLB-KO mice were used to preclude ancillary effects of CaMKII mediated by phospholamban phosphorylation. In both WT and PLB-KO myocytes, Ca²⁺ spark frequency was increased by both preactivated exogenous CaMKII and endogenous CaMKII. This effect was abolished by CaMKII inhibitor peptides. In contrast, protein kinase A catalytic subunit also enhanced Ca²⁺ spark frequency in WT, but had no effect in PLB-KO. Both endogenous and exogenous CaMKII increased SR Ca²⁺ content in WT (presumably via PLB phosphorylation), but not in PLB-KO. Exogenous calmodulin decreased Ca²⁺ spark frequency in both WT and PLB-KO (K_0.5 100 nmol/L). Endogenous CaMKII (at 500 nmol/L [Ca²⁺]) phosphorylated RyR as completely in <4 minutes as the maximum achieved by preactivated exogenous CaMKII. After CaMKII activation Ca²⁺ sparks were longer in duration, and more frequent propagating SR Ca²⁺ release events were observed. We conclude that CaMKII-dependent phosphorylation of RyR by endogenous associated CaMKII (but not PKA-dependent phosphorylation) increases resting SR Ca²⁺ release or leak. Moreover, this may explain the enhanced SR diastolic Ca²⁺ leak and certain triggered arrhythmias seen in heart failure.

Key Words: cardiac myocytes • sarcoplasmic reticulum • Ca spark • CaMKII

Related Article:

Phosphorylation of the Cardiac Ryanodine Receptor by Ca²⁺/Calmodulin-Dependent Protein Kinase II: The Dominating Twin of Protein Kinase A?

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