Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation

Ventricular fibrillation leading to sudden cardiac death can occur even in the absence of structural heart disease, One form of this so-called idiopat hic ventricular fibrillation (IVF) is characterized by ST segment elevation (STE) in the electrocardiogram. Recently we found that NF with STE is link ed to mutations of SCN5A, the gene encoding the cardiac sodium channel alph a -subunit. Two types of defects were identified: loss-of-function mutation s that severely truncate channel proteins and missense mutations (e.g. a do uble mutation, R1232W and T1620M) that cause only minor changes in channel gating. Here we show that co-expression of the R1232W+T1620M missense mutan t alpha -subunits in a mammalian cell line stably transfected with human so dium channel beta (1)-subunits results in a phenotype similar to that of th e truncation mutants, In the presence of beta (1) subunits the expression o f both ionic currents and alpha -subunit-specific, immunoreactive protein w as markedly suppressed after transfection of mutant, but not wild-type alph a -subunits when cells were incubated at physiological temperature. Express ion was partially restored by incubation at reduced temperatures. Our resul ts reconcile two classes of IVF mutations and support the notion that a red uction in the amplitude of voltage-gated sodium conductance is the primary cause of IVF. (C) 2000 Academic Press.