Scn3b knockout mice exhibit abnormal sino‐atrial and cardiac conduction properties

Abstract

AimIn contrast to extensive reports on the roles of Nav1.5 α-subunits, there have been few studies associating the β-subunits with cardiac arrhythmogenesis. We investigated the sino-atrial and conduction properties in the hearts of Scn3b−/− mice.MethodsThe following properties were compared in the hearts of wild-type (WT) and Scn3b−/− mice: (1) mRNA expression levels of Scn3b, Scn1b and Scn5a in atrial tissue. (2) Expression of the β3 protein in isolated cardiac myocytes. (3) Electrocardiographic recordings in intact anaesthetized preparations. (4) Bipolar electrogram recordings from the atria of spontaneously beating and electrically stimulated Langendorff-perfused hearts.ResultsScn3b mRNA was expressed in the atria of WT but not Scn3b−/− hearts. This was in contrast to similar expression levels of Scn1b and Scn5a mRNA. Immunofluorescence experiments confirmed that the β3 protein was expressed in WT and absent in Scn3b−/− cardiac myocytes. Lead I electrocardiograms from Scn3b−/− mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts. Spontaneously beating Langendorff-perfused Scn3b−/− hearts demonstrated both abnormal atrial electrophysiological properties and evidence of partial or complete dissociation of atrial and ventricular activity. Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all Scn3b−/− but hardly any WT hearts. Scn3b−/− hearts also demonstrated significantly longer sinus node recovery times than WT hearts.ConclusionThese findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion.

NaV1.5 and Regulatory β Subunits in Cardiac Sodium Channelopathies

“…In addition, they found increased SA node recovery times and inducibility of atrial tachycardia and AF by burst pacing, extending the potential use of these animals as models for sick sinus syndrome (SSS) or AF. 79 In contrast to Scn1b null mice, no neurologic phenotypes were reported, suggesting that the most important functional roles of Scn3b may be in the heart. A recent study resolved the crystal structure of the b3 immunoglobulin domain, revealing that it assembles as a trimer in the crystal asymmetric unit.…”

The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

“…Mutations in SCN2B have been linked to atrial fibrillation (AF) and Brugada syndrome, suggesting a role for β2 in cardiac excitability (Watanabe et al 2009;Riuro et al 2013). Cardiac excitability is also abnormal in Scn3b null mice, suggesting a role for β3 in the heart (Hakim et al 2008(Hakim et al , 2010. Upon programmed electrical stimulation, ventricular tachycardia occurs in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008).…”

“…Upon programmed electrical stimulation, ventricular tachycardia occurs in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008). Scn3b null hearts display atrial tachycardia during atrial burst pacing (Hakim et al 2010). Scn4b has been identified as a modifier gene for Long QT Syndrome (LQTS) resulting from a mutant Scn5a gene (Remme et al 2009).…”

“…Ventricular tachycardia is observed following programmed electrical stimulation in Scn3b null, but not wild-type, Langendorff-perfused hearts (Hakim et al 2008). In hearts paced using atrial burst pacing, Scn3b null hearts were susceptible to atrial tachycardia (Hakim et al 2010). A genetic modifier screen identified SCN4B as a genetic modifier for phenotype severity in a mouse model of an SCN5A allele which results in conduction disease and Brugada syndrome with variable severity in patients (Remme et al 2009).…”

Disease Caused by Mutations in NaV-β Subunit Genes

“…21 No other primary mutations in Na V -interacting subunits have been reported in humans with cardiac conduction disorders, despite the fact that several studies in mice found a crucial role of these proteins in the cardiac conduction system. SCN3B-knockout mice exhibit important intracardiac conduction abnormalities, 30 and, interestingly, in the SCN5A-1798insD mutant mice, differential expression of b4 was found to contribute to strain-dependent conduction defect. 31…”