(Circulation. 2002;105:272.)
© 2002 American Heart Association, Inc.
Editorials |
Progression of Heart Failure
Is Protein Kinase A Hyperphosphorylation of the Ryanodine Receptor a Contributing Factor?
From the Center for Molecular Cardiology, Department of Pharmacology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians & Surgeons, Rm 9-401, 630 W 168th St, New York, NY 10032. E-mail arm42@columbia.edu
Key Words: Editorials • sarcoplasmic reticulum • calcium • excitation • contractility
The cardiac ryanodine receptor (RyR2)/Ca2+ release channel on the sarcoplasmic reticulum (SR) is regulated by evolutionarily highly conserved signaling pathways that control excitation-contraction (EC) coupling in the heart. Phosphorylation of RyR2 by cAMP-dependent protein kinase (PKA) plays a key role in regulating the channel in response to stress via activation of the sympathetic nervous system (the "fight-or-flight response").1 Maladaptive PKA hyperphosphorylation of RyR2 in failing hearts alters channel function, which may cause depletion of SR Ca2+ and diastolic release of SR Ca2+. This can initiate delayed afterdepolarizations that trigger ventricular arrhythmias.1 Mutations in RyR2 recently have been identified in patients with catecholaminergic induced sudden cardiac death (SCD).2–4 There may be a direct link between the PKA hyperphosphorylation of RyR2 that occurs during the progression of heart failure and fatal cardiac arrhythmias.
Regulation of cardiac EC coupling by the release of Ca2+ from the SR via RyR2 in cardiomyocytes, known as Ca2+-induced Ca2+ release (CICR), has been appreciated for more than a decade.5,6 Furthermore, it is well known that the amplitude of the Ca2+ transient generated by SR Ca2+ release determines contractile force in cardiomyocytes. The systems that regulate SR Ca2+ release include: (1) the triggers (predominantly Ca2+ influx through the voltage-gated Ca2+ channel on the plasma membrane); (2) the SR Ca2+ release channel or type 2 RyR2; and (3) the SR Ca2+ reuptake pump (SERCA2a) and its regulator phospholamban. These systems (trigger, release, and reuptake) are modulated by signaling pathways, including the ß-adrenergic receptor (ß-AR) signaling pathway (ie,
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