title: Functional suppression of sodium channels by beta(1)-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 alpha -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 alpha -subunits in a mammalian cell line stably transfected with human sodium channel beta(1)-subunits results in a phenotype similar to that of the truncation mutants. In the presence of beta(1)subunits the expression of both ionic currents and alpha -subunit-specific, immunoreactive protein was markedly suppressed after transfection of mutant, but not wild-type alpha -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.
authors.affiliation: Rammelkamp Center for Education and Research, Case Western Reserve University, Cleveland, OH 44109, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wan
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: G E
authors.initials: GE
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D015151:Immunoblotting; D007477:Ions; D007700:Kinetics; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D014693:Ventricular Fibrillation / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology
chemical_list: D018076:DNA, Complementary; D007477:Ions; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels