Scn1b deletion leads to increased tetrodotoxin‐sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts. (17th September 2014)

• Record Type: Journal Article
• Authors: Lin, Xianming; O'Malley, Heather; Chen, Chunling; Auerbach, David; Foster, Monique; Shekhar, Akshay; Zhang, Mingliang; Coetzee, William; Jalife, José; Fishman, Glenn I.; Isom, Lori; Delmar, Mario
• Is Part Of: Journal of physiology. Volume 593:Number 6(2015:Mar.)
• Page Start: 1389
• Page End: 1407
• Publication Date: 2014-09-17
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2014.277699
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6322-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6322-list-0001" list-type="bullet"> <list-item> <p>Na<sup>+</sup> current (<italic>I</italic><sub>Na</sub>) results from the integrated function of a molecular aggregate (the voltage‐gated Na<sup>+</sup> channel complex) that includes the β subunit family.</p> </list-item> <list-item> <p>Mutations or rare variants in <italic>Scn1b</italic> (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy.</p> </list-item> <list-item> <p>We used <italic>Scn1b</italic> null mice to understand better the relation between <italic>Scn1b</italic> expression, and cardiac electrical function.</p> </list-item> <list-item> <p>Loss of <italic>Scn1b</italic> caused, among other effects, increased amplitude of tetrodotoxin‐sensitive <italic>I</italic><sub>Na</sub>, delayed after‐depolarizations, triggered beats, delayed Ca<sup>2+</sup> transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca<sup>2+</sup> homeostasis were prevented by 100 n<sc>m</sc> tetrodotoxin.</p> </list-item> <list-item> <p>We propose that life‐threatening arrhythmias in patients with mutations in <italic>Scn1b</italic>, a gene classically defined as ancillary to the Na<sup>+</sup> channel α subunit, can be partly consequent to disrupted intracellular Ca<sup>2+</sup> homeostasis.</p> </list-item> </list> </p> </sec> <sec id="tjp6322-sec-0020" sec-type="section"> <title>Abstract</title> <p>Na<sup>+</sup> current (<italic>I</italic><sub>Na</sub>) is determined not only by the properties of the pore‐forming voltage‐gated Na<sup>+</sup> 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 <italic>Scn1b</italic> (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 <italic>Scn1b</italic> null mouse models to understand better the relation between <italic>Scn1b</italic> expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of <italic>Scn1b</italic> in juvenile null animals resulted in increased tetrodotoxin‐sensitive <italic>I</italic><sub>Na</sub> but only in the cell midsection, even before full T‐tubule formation; the latter occurred concurrent with increased message abundance for the neuronal <italic>Scn3a</italic> mRNA, suggesting increased abundance of tetrodotoxin‐sensitive Na<sub>V</sub>1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac‐specific adult <italic>Scn1b</italic> null animals showed increased <italic>Scn3a</italic> message, prolonged action potential repolarization, presence of delayed after‐depolarizations and triggered beats, delayed Ca<sup>2+</sup> transients and frequent spontaneous Ca<sup>2+</sup> release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca<sup>2+</sup> homeostasis were prevented by 100 n<sc>m</sc> tetrodotoxin. Our results suggest that life‐threatening arrhythmias in patients with mutations in <italic>Scn1b</italic>, a gene classically defined as ancillary to the Na<sup>+</sup> channel α subunit, can be partly consequent to disrupted intracellular Ca<sup>2+</sup> homeostasis in ventricular myocytes.</p> </sec> </abstract>