Functional Suppression of Sodium Channels by β1-Subunits as a Molecular Mechanism of Idiopathic Ventricular Fibrillation☆

Abstract Ventricular fibrillation leading to sudden cardiac death can occur even in the absence of structural heart disease. One form of this so-called idiopathic ventricular fibrillation (IVF) is characterized by ST segment elevation (STE) in the electrocardiogram. Recently we found that IVF with STE is linked to mutations of SCN5A , the gene encoding the cardiac sodium channel α -subunit. Two types of defects were identified: loss-of-function mutations that severely truncate channel proteins and missense mutations (e.g. a double mutation, R1232W and T1620M) that cause only minor changes in channel gating. Here we show that co-expression of the R1232W+T1620M missense mutant α -subunits in a mammalian cell line stably transfected with human sodium channel β 1 -subunits results in a phenotype similar to that of the truncation mutants. In the presence of β 1 subunits the expression of both ionic currents and α -subunit-specific, immunoreactive protein was markedly suppressed after transfection of mutant, but not wild-type α -subunits when cells were incubated at physiological temperature. Expression was partially restored by incubation at reduced temperatures. Our results reconcile two classes of IVF mutations and support the notion that a reduction in the amplitude of voltage-gated sodium conductance is the primary cause of IVF.