Copyright © 2005, European Society of Cardiology
Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization
aDepartment of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada, H1T 1C8
bDepartment of Anesthesiology, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
* Corresponding author. University of Montreal, Montreal Heart Institute, Department of Medicine, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8. Tel.: +1 514 376 3330; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org
Background: Atrial fibrillation (AF) is a common acquired arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (SNP, A/G) at position 112 in the KCNE1 gene, resulting in a glycine/serine amino acid substitution at position 38 of the minK peptide, was associated with AF occurrence (AF more frequent with minK38G); however, the functional effect of this SNP is unknown.
Methods and Results: We used patch clamp recording, confocal microscopy and protein biochemistry to study the effect of this SNP on delayed-rectifier current expression and mathematical simulation to identify potential functional consequences. The density of slow delayed rectifier current (IKs) resulting from co-expression with KvLQT1 was smaller with minK38G (e.g. at +10 mV: 50 ± 7 pA/pF in Chinese hamster ovary (CHO) cells, 45 ± 14 pA/pF for COS-7 cells) compared to minK38S (93 ± 17 pA/pF, 104 ± 23 pA/pF, respectively, P<0.05 for each). IKs kinetics and voltage-dependence were unaffected. Currents resulting from co-expression of human ether-a-go-go-related gene (HERG) were similar for minK38G and minK38S, e.g. upon repolarization from +10 to –50 mV: tail currents 23 ± 4 pA/pF versus 22 ± 5 pA/pF (P = ns). KvLQT1 membrane immunofluorescence was less in CHO cells co-expressing minK38G versus minK38S, and surface expression of KvLQT1, as determined by labelling with streptavidin/biotin, was increased with minK38S co-expression. Computer simulations with a human atrial action potential model predicted that the minK38G SNP would slightly prolong the atrial action potential and reduce the frequency for alternans behaviour. In the presence of reduced repolarization reserve, these effects were enhanced and under specific conditions early afterdepolarizations occurred.
Conclusions: The minK38G isoform is associated with reduced IKs, likely due to decreased KvLQT1 membrane expression. This study reveals a novel amino acid determinant of the minK-KvLQT1 interaction, and if the role of minK38G in AF is confirmed, would suggest mechanistic heterogeneity in genetic determinants of AF.
KEYWORDS Arrhythmia (mechanisms); Gene polymorphisms; Ion channels; K-channel; Repolarization
1 Both authors contributed equally to this work.
Time for primary review 38 days
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