Document Detail


Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f).
MedLine Citation:
PMID:  18603586     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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; Geoffrey W Abbott
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-07-04
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  22     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-01     Completed Date:  2008-10-21     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3648-60     Citation Subset:  IM    
Affiliation:
Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10065, USA.
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MeSH Terms
Descriptor/Qualifier:
Anesthetics, Inhalation / pharmacology
Animals
Heart Conduction System / drug effects,  metabolism,  physiopathology*
Heart Ventricles / drug effects,  metabolism,  pathology,  physiopathology*
Humans
Immunoprecipitation
Kv1.5 Potassium Channel / metabolism
Long QT Syndrome / genetics,  metabolism,  pathology,  physiopathology*
Methyl Ethers / pharmacology
Mice
Mice, Mutant Strains
Muscle Cells / metabolism,  pathology
Potassium Channels, Voltage-Gated / genetics,  metabolism*
Sequence Deletion*
Shal Potassium Channels / metabolism
Grant Support
ID/Acronym/Agency:
HL081336/HL/NHLBI NIH HHS; R01 HL079275/HL/NHLBI NIH HHS; R01 HL079275/HL/NHLBI NIH HHS; R01 HL081336/HL/NHLBI NIH HHS; RG/05/009//British Heart Foundation
Chemical
Reg. No./Substance:
0/Anesthetics, Inhalation; 0/Kcne2 protein, mouse; 0/Kv1.5 Potassium Channel; 0/Methyl Ethers; 0/Potassium Channels, Voltage-Gated; 0/Shal Potassium Channels; 28523-86-6/sevoflurane
Comments/Corrections

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