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(Circulation Research. 2004;94:418.)
© 2004 American Heart Association, Inc.

Editorials

NADH, a New Player in the Cardiac Ryanodine Receptor?

Gerhard Meissner

From the Departments of Biochemistry and Biophysics, and Cell and Molecular Physiology, 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

Key Words: cardiac muscle Ca²⁺ release • redox modulation • NADH oxidase

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

In this issue of Circulation Research, Cherednichenko et al¹ describe an NADH oxidase activity that regulates the ryanodine receptor ion channel (RyR2) in cardiac muscle. Mammalian tissues express three closely related 560-kDa ryanodine receptors (RyRs) encoded by separate genes. RyR1 is the predominant isoform in skeletal muscle, and RyR2 predominates in heart. RyR3 is widely expressed at low levels. RyRs control diverse cellular functions by releasing Ca²⁺ ions from intracellular membrane-bound Ca²⁺ stores. In cardiac muscle, release of Ca²⁺ from the sarcoplasmic reticulum (SR) into the cytoplasm leads to muscle contraction. Released Ca²⁺ returns to SR by an ATP-dependent Ca²⁺ pump, resulting in muscle relaxation. The RyRs are regulated by myriad pathways through small diffusible molecules such as Ca²⁺, Mg²⁺, and ATP and by calmodulin, kinases, and phosphatases.^2,3

The RyRs are also targets for redox active molecules (Figure).^3,4 Active muscle produces reactive oxygen and reactive nitrogen species that modulate RyR2. Changes in oxygen tension or the ratio of reduced to oxidized glutathione modulate RyR2 activity by reducing and oxidizing cysteine residues (J. Sun and G. Meissner, unpublished data). RyR2 is endogenously S-nitrosylated,⁵ and an association of RyR2 with neuronal nitric oxide synthase has been described,⁶ suggesting NO and related molecules are physiological modulators of cardiac muscle excitation-contraction coupling. The study by Cherednichenko et al¹ along with two recent reports^7,8 provide evidence for an additional redox-sensing mechanism in cardiac muscle. An NADH oxidase is shown to modulate RyR2 through the cytosolic NADH/NAD⁺ redox potential in cardiac . . . [Full Text of this Article]

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