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J. Biol. Chem., Vol. 281, Issue 50, 38498-38506, December 15, 2006

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Calcineurin Increases Cardiac Transient Outward K⁺ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits^*

Nanling Gong¹, Ilona Bodi^¶, Carsten Zobel^||, Arnold Schwartz^¶, Jeffery D. Molkentin^**2, and Peter H. Backx, Career Investigator of the Heart and Stroke Foundation of Ontario³

From the Departments of Physiology and Medicine, Heart and Stroke/Richard Lewar Centre of Excellence, and the Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario M5S 3E2, Canada, the ^¶Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, the ^||Department of Internal Medicine III, University of Cologne, Cologne 50924, Germany, and the ^**Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229

Fast transient outward potassium currents (I_to,f) are critical determinants of regional heterogeneity of cardiomyocyte repolarization as well as cardiomyocyte contractility. Additionally, I_to,f densities are markedly down-regulated in cardiac hypertrophy and heart disease, conditions associated with activation of the serine/threonine phosphatase calcineurin (Cn). In this study, we investigated the regulation of I_to,f expression by Cn in cultured neonatal rat ventricular myocytes (NRVMs) with and without ₁-adrenoreceptor stimulation with phenylephrine (PE). Overexpression of constitutively active Cn in NRVMs induced hypertrophy and caused profound increases in I_to,f density as well as Kv4.2 mRNA and protein expression and promoter activity, without affecting Kv4.3 or KChIP2 levels. The effects of Cn on hypertrophy, I_to,f, and Kv4.2 transcription were associated with NFAT activation and were abrogated by NFAT inhibition. Despite activating Cn and inducing hypertrophy in NRVMs, PE resulted in profound down-regulation of I_to,f densities as well as Kv4.2, Kv4.3, and KChIP2 expression. Although hypertrophy and NFAT activation were inhibited by the Cn inhibitory peptide CAIN, I_to,f and Kv4.2 expression were further reduced by CAIN, whereas Cn overexpression eliminated PE-induced reductions in I_to,f and Kv4.2 expression without affecting Kv4.3 or KChIP2 levels. We conclude that Cn increases cardiac I_to,f densities by positively regulating Kv4.2 gene transcription. Consistent with this conclusion, we found that I_to,f was increased in myocytes isolated from young mice overexpressing Cn prior to the development of heart disease. This positive regulation of Kv4.2 transcription by Cn activation is expected to minimize the reductions in I_to,f and Kv4.2 expression observed in hypertrophic cardiomyocytes.

Received for publication, August 14, 2006 , and in revised form, September 27, 2006.

^* This work was supported in part by the Canadian Institutes of Health Research (to P. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by postdoctoral fellowships from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research Tailored Advanced Collaborative Training in Cardiovascular Science Program, and the Faculty of Medicine at the University of Toronto.

² Established Investigator of the American Heart Association.

³ To whom correspondence should be addressed: Heart and Stroke/Richard Lewar Centre of Excellence, Fitzgerald Bldg., 150 College St., Toronto, Ontario M5S 3E2, Canada. Tel.: 416-949-8112; Fax: 416-949-8380; E-mail: p.backx{at}utoronto.ca.

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