Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Abstract

In neurons, voltage-gated sodium channel β subunits regulate the expression levels, subcellular localization, and electrophysiological properties of sodium channel α subunits. However, the contribution of β subunits to sodium channel function in heart is poorly understood. We examined the role of β1 in cardiac excitability using Scn1b null mice. Compared to wildtype mice, electrocardiograms recorded from Scn1b null mice displayed longer RR intervals and extended QT c intervals, both before and after autonomic block. In acutely dissociated ventricular myocytes, loss of β1 expression resulted in a ~1.6-fold increase in both peak and persistent sodium current while channel gating and kinetics were unaffected. Na v 1.5 expression increased in null myocytes ~1.3 fold. Action potential recordings in acutely dissociated ventricular myocytes showed slowed repolarization, supporting the extended QT c interval. Immunostaining of individual myocytes or ventricular sections revealed no discernable alterations in the localization of sodium channel α or β subunits, ankyrin B , ankyrin G , N-cadherin, or connexin-43. Together, these results suggest that β1 is critical for normal cardiac excitability and loss of β1 may be associated with a long QT phenotype.

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

“…Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12,13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14)(15)(16)(17)(18)(19)(20)(21).…”

“…TTX-R Na v 1.5 channels also are upregulated in Scn1b null ventricular myocytes (12). Consequently, we investigated whether TTX-R channels are up-regulated in CGNs in the absence of β1.…”

“…Given that Scn1b mutations result in channelopathies in vivo (12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and that β1-mediated neurite outgrowth in CGNs requires I Na and Na v 1.6, we postulated that β1 might regulate electrical excitability in the cerebellum. To test this, we recorded APs in P12-13 WT and Scn1b null CGNs in cerebellar slices by whole-cell patch clamping.…”

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

“…The stimulus to elicit an AP (threshold current) was determined by application of 3-ms test pulses every 2.5 s, starting at 0.1 nA and increasing by 0.1 nA until an AP was observed. Subsequent APs were evoked by application of 12 3-ms test pulses at 1.5ϫ threshold (14). DRGs were paced at 1, 10, 6.6, 3.3, and finally 1 Hz, and for every cell the same sequence of protocols was used.…”

Mouse models of SCN5A-related cardiac arrhythmias

“…The cardiac electrophysiological phenotype of a mouse model invalidated for Scn1b markedly differed from the phenotype of the patients presented above (Lopez-Santiago et al, 2007). Compared to wild-type mice, Scn1b knockout mice exhibited lower heart rates and prolonged QT intervals, without any signs of conduction disease.…”