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(Circulation Research. 2007;100:399.)
© 2007 American Heart Association, Inc.

Cellular Biology

Ca²⁺/Calmodulin Kinase II-Dependent Phosphorylation of Ryanodine Receptors Suppresses Ca²⁺ Sparks and Ca²⁺ Waves in Cardiac Myocytes

Dongmei Yang, Wei-Zhong Zhu, Bailong Xiao, Didier X.P. Brochet, S.R. Wayne Chen, Edward G. Lakatta, Rui-Ping Xiao, Heping Cheng

From the Laboratory of Cardiovascular Science (D.Y., W.-Z.Z., D.X.P.B., E.G.L., R.-P.X., H.C.), National Institute on Aging, NIH, Baltimore, Md; and Cardiovascular Research Group (B.X., S.R.W.C.), Department of Physiology and Biophysics, University of Calgary, Canada; and Institute of Molecular Medicine (R.-P.X. and H.C.), Peking University, Beijing, China. Present address for D.X.P.B.: Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Md. Present address for R.-P.X. and H.C.: Institute of Molecular Medicine, Peking University, Beijing, China.

Correspondence to Heping Cheng, PhD, Institute of Molecular Medicine, Peking University, Beijing 100871, China. E-mail chengp{at}pku.edu.cn; and Wei-Zhong Zhu, MD, PhD, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224. E-mail zhuw@grc.nia.nih.gov

The multifunctional Ca²⁺/calmodulin-dependent protein kinase II _C (CaMKII_C) is found in the macromolecular complex of type 2 ryanodine receptor (RyR2) Ca²⁺ release channels in the heart. However, the functional role of CaMKII-dependent phosphorylation of RyR2 is highly controversial. To address this issue, we expressed wild-type, constitutively active, or dominant-negative CaMKII_C via adenoviral gene transfer in cultured adult rat ventricular myocytes. CaMKII-mediated phosphorylation of RyR2 was reduced, enhanced, or unaltered by dominant-negative, constitutively active, or wild-type CaMKII_C expression, whereas phosphorylation of phospholamban at Thr17, an endogenous indicator of CaMKII activity, was at 73%, 161%, or 115% of the control group expressing ß-galactosidase (ß-gal), respectively. In parallel with the phospholamban phosphorylation, the decay kinetics of global Ca²⁺ transients was slowed, accelerated, or unchanged, whereas spontaneous Ca²⁺ spark activity was hyperactive, depressed, or unchanged in dominant-negative, constitutively active, or wild-type CaMKII_C groups, respectively. When challenged by high extracellular Ca²⁺, both wild-type and constitutively active CaMKII_C protected the cells from store overload-induced Ca²⁺ release, manifested by a 60% suppression of Ca²⁺ waves (at 2 to 20 mmol/L extracellular Ca²⁺) in spite of an elevated sarcoplasmic reticulum Ca²⁺ content, whereas dominant-negative CaMKII_C promoted Ca²⁺ wave production (at 20 mmol/L Ca²⁺) with significantly depleted sarcoplasmic reticulum Ca²⁺. Taken together, our data support the notion that CaMKII_C negatively regulates RyR2 activity and spontaneous sarcoplasmic reticulum Ca²⁺ release, thereby affording a negative feedback that stabilizes local and global Ca²⁺-induced Ca²⁺ release in the heart.

Key Words: Ca²⁺/calmodulin-dependent protein kinase II • Ryanodine receptor • Ca²⁺ sparks • Ca²⁺ waves • Ca²⁺-induced Ca²⁺ release

Related Article:

Does Ca²⁺/Calmodulin-Dependent Protein Kinase _c Activate or Inhibit the Cardiac Ryanodine Receptor Ion Channel?

Naohiro Yamaguchi and Gerhard Meissner
Circ. Res. 2007 100: 293-295. [Full Text] [PDF]

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