Published online before print January 8, 2009, doi: 10.1161/CIRCRESAHA.108.181651
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Submitted on June 16, 2008
Revised on December 8, 2008
Accepted on December 30, 2008
miR-1 Overexpression Enhances Ca2+ Release and Promotes Cardiac Arrhythmogenesis by Targeting PP2A Regulatory Subunit B56
and Causing CaMKII-Dependent Hyperphosphorylation of RyR2
Dmitry Terentyev *;
From the Davis Heart and Lung Research Institute (D.T., A.E.B., R.T., M.M.M., G.E.M., D.E.K., D.S.F., T.S.E., S.G.), Ohio State University, Columbus; and Cardiovascular Research Institute (M.A.), Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark.
* To whom correspondence should be addressed. E-mail: Dmitry.Terentyev{at}osumc.edu.
MicroRNAs are small endogenous noncoding RNAs that regulate protein expression by hybridization to imprecise complementary sequences of target mRNAs. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. However, the specific molecular targets and cellular mechanisms involved in the action of miR-1 in the heart are only beginning to emerge. In this study we investigated the effects of increased expression of miR-1 on excitation–contraction coupling and Ca2+ cycling in rat ventricular myocytes using methods of electrophysiology, Ca2+ imaging and quantitative immunoblotting. Adenoviral-mediated overexpression of miR-1 in myocytes resulted in a marked increase in the amplitude of the inward Ca2+ current, flattening of Ca2+ transients voltage dependency, and enhanced frequency of spontaneous Ca2+ sparks while reducing the sarcoplasmic reticulum Ca2+ content as compared with control. In the presence of isoproterenol, rhythmically paced, miR-1–overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca2+, events that occurred rarely in control myocytes under the same conditions. The effects of miR-1 were completely reversed by the CaMKII inhibitor KN93. Although phosphorylation of phospholamban was not altered, miR-1 overexpression increased phosphorylation of the ryanodine receptor (RyR2) at S2814 (CaMKII) but not at S2808 (protein kinase A). Overexpression of miR-1 was accompanied by a selective decrease in expression of the protein phosphatase PP2A regulatory subunit B56
involved in PP2A targeting to specialized subcellular domains. We conclude that miR-1 enhances cardiac excitation–contraction coupling by selectively increasing phosphorylation of the L-type and RyR2 channels via disrupting localization of PP2A activity to these channels.
Key words: ryanodine receptor • miR-1 CaMKII • PP2A • arrhythmia
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