Electrophysiological Function Of Voltage-gated Sodium Channel ?2 Subunit In The Heart

PURPOS:Mutations in SCN2B,encoding voltage-gated sodium channel ?2-subunits,are associated with human cardiac arrhythmias,including atrial fibrillation and Brugada syndrome.Because of this,we propose that ?2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivoMETHODS AND RESULT:To understand the pathophysiological roles of ?2 in the heart,we investigated the cardiac phenotype of Scn2b null mice.We observed reduced sodium and potassium current densities in ventricular myocytes,as well as conduction slowing in the right ventricular outflow tract region.Functional reentry,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.Similar to the previous work in neurons,the major function of ?2-subunits in the ventricle is to chaperone voltage-gated sodium channel?-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 with wild type.Scn2b null hearts were more susceptible to atrial fibrillation,had increased levels of fibrosis,and higher repolarization dispersion than wild-type littermatesCONCLUSIONGenetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias,consistent with reported SCN2B mutations in human patients.