Department of Anesthesiology

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Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f).

TitleTargeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f).
Publication TypeJournal Article
Year of Publication2008
AuthorsRoepke TK, Kontogeorgis A, Ovanez C, Xu X, Young JB, Purtell K, Goldstein PA, Christini DJ, Peters NS, Akar FG, Gutstein DE, Lerner DJ, Abbott GW
JournalFASEB J
Volume22
Issue10
Pagination3648-60
Date Published2008 Oct
ISSN1530-6860
KeywordsAnesthetics, Inhalation, Animals, Heart Conduction System, Heart Ventricles, Humans, Immunoprecipitation, Kv1.5 Potassium Channel, Long QT Syndrome, Methyl Ethers, Mice, Mice, Mutant Strains, Muscle Cells, Potassium Channels, Voltage-Gated, Sequence Deletion, Shal Potassium Channels
Abstract

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 alpha subunits, was also diminished, by approximately 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 alpha subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.

DOI10.1096/fj.08-110171
Alternate JournalFASEB J.
PubMed ID18603586
PubMed Central IDPMC2537427
Grant ListHL081336 / HL / NHLBI NIH HHS / United States
R01 HL079275 / HL / NHLBI NIH HHS / United States
R01 HL079275 / HL / NHLBI NIH HHS / United States
R01 HL081336 / HL / NHLBI NIH HHS / United States
RG/05/009 / / British Heart Foundation / United Kingdom