Scn1b deletion leads to increased tetrodotoxin‐sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts

Abstract

Na+ current (INa) is determined not only by the properties of the pore‐forming voltage‐gated Na+ channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC β subunit family. Mutations or rare variants in Scn1b (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin‐sensitive INa but only in the cell midsection, even before full T‐tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin‐sensitive NaV1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac‐specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after‐depolarizations and triggered beats, delayed Ca2+ transients and frequent spontaneous Ca2+ release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca2+ homeostasis were prevented by 100 nm tetrodotoxin. Our results suggest that life‐threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na+ channel α subunit, can be partly consequent to disrupted intracellular Ca2+ homeostasis in ventricular myocytes.