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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
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Mouse ERG K(+) channel clones reveal differences in protein trafficking and function
Eric C Lin1, Brooke M Moungey1, Evi Lim1
1Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI (E.C.L., B.M.M., E.L., S.P.C., C.L.A., J.W.K., J.C.M., S.Y.B., C.T.J.).
Journal of the American Heart Association
|December 16, 2014
Summary
Mouse ether-a-go-go-related gene 1a (mERG1a) channel variants show differences in protein trafficking and function. The mERG-London variant is trafficking deficient, supporting structure-function relationships in long-QT syndrome type 2.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Genetics
Background:
- Mouse ether-a-go-go-related gene 1a (mERG1a) encodes mERG K(+) channels in cardiomyocytes, analogous to human hERG channels that conduct IKr.
- Mutations in hERG channels are linked to congenital long-QT syndrome type 2, primarily due to reduced surface membrane expression of trafficking-deficient channels.
- Three mERG cDNA sequences (mERG-London, mERG-Waterston, mERG-Nie) differing by 1-4 amino acids have been reported.
Purpose of the Study:
- To characterize three mERG channel variants to determine if they exhibit distinct protein trafficking and biophysical functions.
- To investigate the postulation that sequence variations influence mERG channel behavior, drawing parallels with hERG channel findings in long-QT syndrome type 2.
Main Methods:
- Expression of three mERG variants and hERG channels in HEK293 cells and neonatal mouse cardiomyocytes.
- Analysis using Western blot and whole-cell patch clamp electrophysiology.
- Comparison of findings with sequencing data from the Welcome Trust Sanger Institute Mouse Genomes Project (WTSIMGP).
Main Results:
- The mERG-London channel, with substitutions in ordered structural regions, demonstrated trafficking deficiency.
- This trafficking deficiency in mERG-London was amenable to temperature-dependent and pharmacological correction.
- Distinct voltage-dependence of channel gating was observed among the three mERG channel variants.
- The mERG-Nie clone aligns with the wild-type mouse sequence and physiology when compared to WTSIMGP data.
Conclusions:
- Sequence variations in highly ordered structural regions of mERG channels can lead to trafficking deficiencies, mirroring hERG channel behavior in long-QT syndrome type 2.
- The mERG-Nie clone likely represents the wild-type sequence, while mERG-London exhibits functional and trafficking defects.
- Substrain-specific sequence differences in mERG channels appear common in mice, as suggested by WTSIMGP analysis.
