This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/4/514    most recent CIRCRESAHA.108.181651v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Terentyev, D. Articles by Györke, S. Search for Related Content PubMed PubMed Citation Articles by Terentyev, D. Articles by Györke, S. Related Collections Arrythmias-basic studies Calcium cycling/excitation-contraction coupling Related Article

(Circulation Research. 2009;104:514.)
© 2009 American Heart Association, Inc.

Cellular Biology

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, Andriy E. Belevych, Radmila Terentyeva, Mickey M. Martin, Geraldine E. Malana, Donald E. Kuhn, Maha Abdellatif, David S. Feldman, Terry S. Elton, Sandor Györke

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.

Correspondence to Dmitry Terentyev, PhD, Department of Physiology and Cell Biology, Ohio State University, DHLRI 501, 473 West 12th Ave, Columbus, OH 43210. USA. Phone: +1 614 2923944. Fax:+1 614 247 7799. 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 dependence, 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 (Ca²⁺/calmodulin-dependent protein kinase) 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

Related Article:

Ca²⁺ Signaling Domains Responsible For Cardiac Hypertrophy and Arrhythmias

Steven R. Houser
Circ. Res. 2009 104: 413-415. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				Y. Lu, Y. Zhang, H. Shan, Z. Pan, X. Li, B. Li, C. Xu, B. Zhang, F. Zhang, D. Dong, et al. MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection Cardiovasc Res, December 1, 2009; 84(3): 434 - 441. [Abstract] [Full Text] [PDF]

				B. Schroen and S. Heymans MicroRNAs and Beyond: The Heart Reveals Its Treasures Hypertension, December 1, 2009; 54(6): 1189 - 1194. [Full Text] [PDF]

				E. M. C. Ohlsson Teague, C. G. Print, and M. L. Hull The role of microRNAs in endometriosis and associated reproductive conditions Hum. Reprod. Update, September 22, 2009; (2009) dmp034v1. [Abstract] [Full Text] [PDF]

				A. Goette Nicotine, atrial fibrosis, and atrial fibrillation: do microRNAs help to clear the smoke? Cardiovasc Res, August 1, 2009; 83(3): 421 - 422. [Full Text] [PDF]

				S. R. Houser Ca2+ Signaling Domains Responsible For Cardiac Hypertrophy and Arrhythmias Circ. Res., February 27, 2009; 104(4): 413 - 415. [Full Text] [PDF]