Published online before print January 18, 2007, doi: 10.1161/01.RES.0000258022.13090.55
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Submitted on June 29, 2006
Revised on December 22, 2006
Accepted on January 4, 2007
Ca2+/Calmodulin Kinase II-Dependent Phosphorylation of Ryanodine Receptors Suppresses Ca2+ Sparks and Ca2+ Waves in Cardiac Myocytes
Dongmei Yang ;
From the Laboratory of Cardiovascular Science (D.Y., W.-Z.Z., D.X.P.B., H.C.), National Institute on Aging, NIH, Baltimore, Md; and Cardiovascular Research Group (B.X., S.R.W.C., E.G.L., R.-P.X.), Department of Physiology and Biophysics, University of Calgary, Canada. 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.
* To whom correspondence should be addressed. E-mail: zhuw{at}grc.nia.nih.gov.
The multifunctional Ca2+/calmodulin-dependent protein kinase II 
C (CaMKIIC) 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 CaMKIIC 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 CaMKIIC expression, whereas phosphorylation of phospholamban at Thr17, an endogenous indicator of CaMKII activity, was at 73%, 161%, or 115% of the control group expressing 
-galactosidase (-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 CaMKIIC groups, respectively. When challenged by high extracellular Ca2+, both wild-type and constitutively active CaMKIIC 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 CaMKIIC promoted Ca2+ wave production (at 20 mmol/L Ca2+) with significantly depleted sarcoplasmic reticulum Ca2+. Taken together, our data support the notion that CaMKIIC 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
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