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(Circulation Research. 2006;99:333.)
© 2006 American Heart Association, Inc.

Editorials

Phosphorylation of the Cardiac Ryanodine Receptor by Ca²⁺/Calmodulin-Dependent Protein Kinase II

The Dominating Twin of Protein Kinase A?

Jens Kockskämper, Burkert Pieske

From the Department of Cardiology and Pneumology, Georg-August-University, Göttingen, Germany.

Correspondence to Burkert Pieske, MD, Department of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. E-mail pieske@med.uni-goettingen.de

See related article, pages 398–406

Key Words: adrenergic regulation • Ca2+/calmodulin-dependent protein kinase II • Ca2+ handling • Ca2+ sparks • protein kinase A phosphorylation • ryanodine receptor

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

	Introduction

 
Excitation-contraction coupling in the heart relies on Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum (SR). Ca²⁺ influx via L-type Ca²⁺ channels during an action potential triggers Ca²⁺ release from the SR via Ca²⁺ release channels, or ryanodine receptors (RyR2). Fine tuning of RyR2-mediated SR Ca²⁺ release is central to cardiac function. When RyR2-mediated Ca²⁺ release increases, the resulting augmentation of the [Ca²⁺]_i transient causes increased contraction. Uncontrolled openings of RyR2 during diastole, on the other hand, may elicit delayed afterdepolarizations and arrhythmias. Dysfunction of RyR2 may occur under certain pathological conditions, eg, excess sympathetic stimulation, and may contribute to such cardiac diseases as heart failure¹ or atrial fibrillation.² Furthermore, mutations in RyR2 can cause stress-induced ventricular tachycardias and sudden death in otherwise healthy individuals.³ Thus, proper regulation and function of RyR2 is essential for adequate cardiac function.

	RyR2: Regulation, Regulation, Regulation

 
Not surprisingly, because of its crucial role in cardiac excitation-contraction coupling, RyR2 activity is highly regulated.⁴ Substances involved in regulation of RyR2 activity include Ca²⁺, Mg²⁺, H⁺, adenine nucleotides, calmodulin, NAD⁺/NADH, nitric oxide, and glycolytic intermediates, to name but a few. The list of molecules regulating RyR2 activity is far from complete and will undoubtedly grow longer as research continues. In addition, RyR2 is regulated by phosphorylation. The protein forms a macromolecular complex with regulatory proteins (notably FKBP12.6), cytoskeletal proteins, adapter proteins, kinases, and phosphatases.^1,5 This allows for tight control and localized regulation of RyR2 activity in the microenvironment of the channel.

	Phosphorylation of RyR2 and Cardiac Disease

 
Regulation of RyR2 activity by . . . [Full Text of this Article]

Related Article:

Ca²⁺/Calmodulin-Dependent Protein Kinase II Phosphorylation of Ryanodine Receptor Does Affect Calcium Sparks in Mouse Ventricular Myocytes

Tao Guo, Tong Zhang, Ruben Mestril, and Donald M. Bers
Circ. Res. 2006 99: 398-406. [Abstract] [Full Text] [PDF]

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