Phosphorylation of the Cardiac Ryanodine Receptor by Ca 2+ /Calmodulin-Dependent Protein Kinase II

Abstract

See related article, pages 398–406 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. 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. Regulation of RyR2 activity by phosphorylation is not only important from a physiological point of view to adjust SR Ca2+ release and, ultimately, cardiac output to the varying demands …