Format

Send to:

Choose Destination
See comment in PubMed Commons below
Biochim Biophys Acta. 2011 Dec;1810(12):1285-93. doi: 10.1016/j.bbagen.2011.07.018. Epub 2011 Aug 10.

Partial restoration of the long QT syndrome associated KCNQ1 A341V mutant by the KCNE1 β-subunit.

Author information

  • 1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Abstract

BACKGROUND:

The A341V mutation in the pore-forming KCNQ1 subunit of the slowly activating delayed-rectifier potassium current (IKs) underlies a common form of the long QT syndrome, and is associated with an unusually severe phenotype. However, there is controversy regarding the underlying mechanism responsible for the clinically observed phenotype. We investigated the biophysical characteristics of A341V in a cardiac environment by utilizing a cardiac cell line, and in particular the impact of the KCNE1 β-subunit.

METHODS:

Whole-cell current were recorded from transiently transfected HL-1 cells, a cardiac cell line. Mutant KCNQ1 and KCNE1 were constructed by site-directed mutagenesis.

RESULTS:

The A341V mutant resulted in a non-functional channel when expressed alone. When co-expressed with wild type KCNE1, A341V produced a slowly activating current, with a smaller current density, slower rates of activation, and a depolarized shift in its activation curve compared to the wild type KCNQ1+KCNE1. Confocal microscopy confirmed the surface expression of GFP-tagged A341V, suggesting a functionally defective protein. A T58A mutation in KCNE1 abolished functional restoration of A341V. Under heterozygous conditions, the expression of A341V+KCNQ1+KCNE1 reduced but did not abolish the electrophysiological changes observed in A341V+KCNE1. A dominant negative effect of A341V was also observed. Action potential simulations revealed that the A341V mutation is arrhythmogenic.

CONCLUSIONS:

The KCNE1 β-subunit partially rescued the non-functional A341V mutant, with electrophysiological properties distinct from the wild type IKs.

GENERAL SIGNIFICANCE:

The severity of the A341V phenotype may be due to a combination of a significant suppression of the IKs with altered biophysical characteristics.

2011 Elsevier B.V. All rights reserved.

PMID:
21854832
[PubMed - indexed for MEDLINE]
PMCID:
PMC3215802
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk