Abstract 11392: Molecular Interplay Between NaV1.5 and Kir2.1 in a Mouse Model of Brugada Syndrome
Introduction: Loss-of-function mutations in SCN5A, the gene coding for the alpha subunit of the cardiac Na+ channel, NaV1.5, give rise to many cases of Brugada syndrome type I (BrS1). Recently, NaV1.5 was shown to interact with the inward rectifier K+ channel protein, Kir2.1 in a macromolecular complex that controls their stability in the cell membrane. Thus, we investigated the role of the molecular interplay between NaV1.5 responsible for INa, and the inward rectifier K+ channel (Kir2.1) responsible for IK1 in male, heterozygous Scn5a mice (Scn5a+/-), which have been previously characterized as a model for BrS1.
Methods and Results: We determined functional expression of NaV1.5 and Kir2.1 in single ventricular myocytes using patch-clamping in the whole-cell configuration. We measured INa and IK1 densities, and resting membrane potential (RMP). We also performed ventricular epicardial optical mapping in isolated, Langendorf-perfused hearts from wildtype (WT) and Scn5a+/- mice to compare their conduction velocities (CVs) and AP durations (APDs). INa density in RV myocytes from Scn5a+/- mice was 50.9% lower than WT (Fig A, p<0.05), with no change in channel biophysical properties. In addition, IK1 density in RV myocytes from Scn5a+/- mice was 22.1% lower (Fig B, p<0.05) and their RMP was 3.8 mV less negative than WT (Fig C, p<0.05). Moreover, Scn5a+/- hearts paced at 150 ms cycle length had a reduced ventricular CV (0.74 ± 0.02 vs. 0.60 ± 0.03 m/s; p<0.05) with no difference in APD (APD80 65.6 ± 4.7 vs. 58.4 ± 2.7 ms; p=NS) compared to WT, respectively.
Conclusion: Genetic disruption of the functional expression of NaV1.5 substantially reduces IK1 in the ventricles of the Scn5a+/- mouse, which depolarizes the RMP and significantly increases the arrhythmogenic potential of the disruption. The results suggest a new paradigm to explain the arrhythmogenic mechanism of NaV1.5 loss of function in BrS1.
- © 2013 by American Heart Association, Inc.