Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels

Abstract

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Keywords: Nav1.5-I141V; dilated cardiomyopathy; erythromelalgia; hyper-excitability; myotonia.

Figure 1

Topology of the pore-forming α-subunit of voltage gated sodium channels.

Figure 2

Schematic representation of the shared mechanism of Na_v1.5 mutations associated with cardiac hyper-excitability. Negative shift of the voltage dependence of activation (A) leading to a negative shift of the sodium window conductance (B).

Figure 3

Molecular dynamics simulation of the WT (left panel) and the p.I141V mutants (right panel) of Na_v1.4 channel. In the presence of the p.I141V mutation, the model predicted the formation of a hydrogen bond (Green arrow) between the S2-Y168 and S4-R225 residues, thus stabilizing the open confirmation of the channel; (From Amarouch et al., 2014).

Figure 4

The functional effect of the p.I141V mutation on the steady-state of activation and inactivation processes of Na_v1.5 channel (left panel). The presence of this mutation induces a negative shift of the voltage dependence of activation. However, this effect was abolished in the presence of the p.Y168F substitution (right panel); (From Amarouch et al., 2014).