Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias

Abstract

Background Mutations in SCN2B, encoding voltage-gated sodium channel (VGSC) β2 subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2 subunits play critical roles in the establishment or maintenance of normal cardiac electrical activity in vivo. Methods and Results To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current density in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional re-entry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild type ventricles, as were levels of Nav1.5 protein, suggesting that similar to previous work in neurons, the major function of β2 subunits in the ventricle is to chaperone VGSC α subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared to wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than WT littermates. Conclusions Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.

Trafficking and localisation to the plasma membrane of Nav1.5 promoted by the β2 subunit is defective due to a β2 mutation associated with Brugada syndrome

“…Their I Na is clearly reduced in ventricles, albeit not in atria. Since SCN5A expression and Na v 1.5 levels were found unaffected, the study concluded that Na v 1.5 surface levels are reduced (Bao et al., ), agreeing with previous data and our current work.…”

Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and Ca2+ transients in murine heart

“…; Bao et al . ). As expected, higher pacing frequencies lead to reduced conduction velocities, further demonstrating physiological responsiveness of the slices (Weber et al .…”

Voltage-Gated Sodium Channel β Subunits and Their Related Diseases

“…Scn2b -null ventricular myocytes show reduced sodium and potassium currents, with conduction slowing in the right ventricle compared to wild-type. Scn2b -null atria had normal levels of sodium current compared to wild-type (Bao et al 2016). Scn3b -null mice also show abnormal cardiac excitability, with ventricular tachycardia from electrical stimulation that is not observed in wild-type mice.…”

“…In contract, Scn2b null atria had normal levels of sodium and potassium currents but increased levels of fibrosis. Lastly, Scn2b -null hearts display increased susceptibility to atrial fibrillation and repolarization dispersion compared to wild-type animals (Bao et al 2016). Scn3b -null mice also show cardiac dysfunction.…”