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(Circulation Research. 2007;100:293.)
© 2007 American Heart Association, Inc.

Editorials

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

Naohiro Yamaguchi, Gerhard Meissner

From the Departments of Biochemistry and Biophysics (N.Y., G.M.), and Cell and Molecular Physiology (G.M.), University of North Carolina, Chapel Hill, NC.

Correspondence to Gerhard Meissner, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260. E-mail meissner@med.unc.edu

See related article, pages 399–407

Key Words: Ca²⁺/calmodulin dependent protein kinase II • cardiac ryanodine receptor • protein phosphorylation • heart failure

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The multifunctional Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) modulates cardiac muscle function by regulating Ca²⁺ transport proteins and nuclear signaling molecules. Aberrant activity of CaMKII is implicated in heart disease. In this issue, Yang et al¹ report that acute overexpression of constitutively active splice variant CaMKII_C phosphorylates the cardiac ryanodine receptor ion channel (RyR2) to decrease the rate of occurrence of local Ca²⁺ release events (Ca²⁺ sparks) and Ca²⁺ waves in cultured rat cardiomyocytes. A dominant negative form of CaMKII_C was shown to have opposite effects.

The cardiac ryanodine receptors are cation selective channels that release Ca²⁺ from an intracellular Ca²⁺ storing compartment, the sarcoplasmic reticulum (SR), during a cardiac muscle action potential, in a process known as excitation-contraction coupling.² Released Ca²⁺ cause cardiac muscle to contract. Sequestration of released Ca²⁺ by the SR Ca²⁺-transporting ATPase and extrusion by the Na⁺-Ca²⁺ exchanger restore the myofibrillar Ca²⁺ concentration from 10^–6 - 10^–5 to 10^–7 M, causing muscle to relax. The RyR2s are regulated by a variety of effectors.³ During a cardiac action potential, closely apposed dihydropyridine-sensitive L-type Ca²⁺ channels in the surface membrane and T-tubule mediate influx of Ca²⁺, which triggers massive release of Ca²⁺ from SR by opening RyR2s. In addition to Ca²⁺, endogenous effectors such as Mg²⁺, ATP, reactive oxygen and nitrogen molecules regulate RyR2. RyR2 is also regulated by calmodulin, cAMP-dependent protein kinase A (PKA), calmodulin-dependent kinase II (CaMKII), protein kinase C, and protein phosphatases 1 and 2A. Phosphorylation of RyR2-Ser2030 by . . . [Full Text of this Article]

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