Document Detail


Mechanism of loss of Kv11.1 K+ current in mutant T421M-Kv11.1-expressing rat ventricular myocytes: interaction of trafficking and gating.
MedLine Citation:
PMID:  23136156     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Type 2 long QT syndrome involves mutations in the human ether a-go-go-related gene (hERG or KCNH2). T421M, an S1 domain mutation in the Kv11.1 channel protein, was identified in a resuscitated patient. We assessed its biophysical, protein trafficking, and pharmacological mechanisms in adult rat ventricular myocytes.
METHODS AND RESULTS: Isolated adult rat ventricular myocytes were infected with wild-type (WT)-Kv11.1- and T421M-Kv11.1-expressing adenovirus and analyzed with the use of patch clamp, Western blot, and confocal imaging techniques. Expression of WT-Kv11.1 or T421M-Kv11.1 produced peak tail current (I(Kv11.1)) of 8.78±1.18 and 1.91±0.22 pA/pF, respectively. Loss of mutant I(Kv11.1) resulted from (1) a partially trafficking-deficient channel protein with reduced cell surface expression and (2) altered channel gating with a positive shift in the voltage dependence of activation and altered kinetics of activation and deactivation. Coexpression of WT+T421M-Kv11.1 resulted in heterotetrameric channels that remained partially trafficking deficient with only a minimal increase in peak I(Kv11.1) density, whereas the voltage dependence of channel gating became WT-like. In the adult rat ventricular myocyte model, both WT-Kv11.1 and T421M-Kv11.1 channels responded to β-adrenergic stimulation by increasing I(Kv11.1).
CONCLUSIONS: The T421M-Kv11.1 mutation caused a loss of I(Kv11.1) through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to β-adrenergic stimulation.
Authors:
Sadguna Y Balijepalli; Evi Lim; Sarah P Concannon; Chen L Chew; Kassandra E Holzem; David J Tester; Michael J Ackerman; Brian P Delisle; Ravi C Balijepalli; Craig T January
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-06
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-11     Completed Date:  2013-02-12     Revised Date:  2013-12-17    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2809-18     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Animals
Ether-A-Go-Go Potassium Channels / genetics*,  physiology*
Female
HEK293 Cells
Humans
Ion Channel Gating / physiology*
Long QT Syndrome / genetics*,  physiopathology
Membrane Potentials / physiology
Mutation, Missense / genetics
Myocytes, Cardiac / cytology,  physiology*
Patch-Clamp Techniques
Potassium / metabolism
Protein Transport / physiology
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, beta / physiology
Transfection / methods
Grant Support
ID/Acronym/Agency:
R01 HD042569/HD/NICHD NIH HHS; R01 HD42569/HD/NICHD NIH HHS; R01 HL060723/HL/NHLBI NIH HHS; R01 HL105713/HL/NHLBI NIH HHS; R01 HL105713/HL/NHLBI NIH HHS; R01 HL60723/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/Receptors, Adrenergic, beta; RWP5GA015D/Potassium
Comments/Corrections

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