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c Activate or Inhibit the Cardiac Ryanodine Receptor Ion Channel?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 399407
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 106 - 105 to
107 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
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