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Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I_K,slow1 and I_to,f

Torsten K. Roepke^*,, Andrianos Kontogeorgis^,||, Christopher Ovanez^#, Xianghua Xu^*,, Jeffrey B. Young^*,, Kerry Purtell^*,, Peter A. Goldstein, David J. Christini^*, Nicholas S. Peters, Fadi G. Akar^#, David E. Gutstein^||,¶, Daniel J. Lerner^** and Geoffrey W. Abbott^*,,1

^* Greenberg Division of Cardiology, Department of Medicine,

Department of Pharmacology, and

Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA;

Department of Cardiology, St. Mary’s Hospital, Imperial College London, London, UK;

^|| Department of Medicine, Division of Cardiology, and

^¶ Department of Cell Biology, New York University School of Medicine, New York, New York, USA;

^# The Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, USA; and

^** FoxHollow Technologies, Redwood City, California, USA

¹Correspondence: Starr 463, Greenberg Division of Cardiology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10065, USA. E-mail: gwa2001{at}med.cornell.edu

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (–/–) ventricles exhibited a 50% reduction in I_K,slow1, generated by Kv1.5—a previously unknown partner for MiRP1. I_to,f, generated by Kv4 subunits, was also diminished, by 25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (–/–) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K⁺ currents and prolonged ventricular APD, kcne2 deletion lengthened the QT_c under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.—Roepke, T. K., Kontogeorgis, A., Ovanez, C., Xu, X., Young, J. B., Purtell, K., Goldstein, P. A., Christini, D. J., Peters, N. S., Akar, F. G., Gutstein, D. E., Lerner, D. J., Abbott, G. W. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I_K,slow1 and I_to,f.

Key Words: cardiac arrhythmia • Kv1.5 • Kv4.2 • long QT syndrome • MiRP1 • potassium channel