Late sodium current blocker GS967 inhibits persistent currents induced by familial hemiplegic migraine type 3 mutations of the SCN1A gene

R Barbieri,P Gavazzo,S Bertelli,M Pusch

doi:10.1186/s10194-019-1056-2

Abstract

BackgroundFamilial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na+ channel Nav1.1, and FHM caused by mutations of SCN1A is named FHM3. For 7 of the 12 known FHM3-causing SCNA1 mutations functional consequences have been investigated, and even if gain of function effect seems to be a predominant phenotype, for several mutations conflicting results have been obtained and the available data do not reveal a univocal FHM3 pathomechanism.MethodsTo obtain a more complete picture, here, we characterized by patch clamp approach the remaining 5 mutations (Q1489H, I1498M, F1499 L, M1500 V, F1661 L) in heterologous expression systems.ResultsWith the exception of I1498M, all mutants exhibited the same current density as WT and exhibited a shift of the steady state inactivation to more positive voltages, an accelerated recovery from inactivation, and an increase of the persistent current, revealing that most FHM3 mutations induce a gain of function. We also determined the effect of GS967, a late Na+ current blocker, on the above mentioned mutants as well as on previously characterized ones (L1649Q, L1670 W, F1774S). GS967 inhibited persistent currents of all SCNA1 FMH3-related mutants and dramatically slowed the recovery from fast inactivation of WT and mutants, consistent with the hypothesis that GS967 specifically binds to and thereby stabilizes the fast inactivated state.Simulation of neuronal firing showed that enhanced persistent currents cause an increase of ionic fluxes during action potential repolarization and consequent accumulation of K+ and/or exhaustion of neuronal energy resources. In silico application of GS967 largely reduced net ionic currents in neurons without impairing excitability.ConclusionIn conclusion, late Na+ current blockers appear a promising specific pharmacological treatment of FHM3.

Highlights

Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura
FHM1 is caused by mutations in the gene encoding the presynaptic neuronal Ca2+ channel Cav2.1, FHM2 is associated with mutations of a glial specific Na-KATPase, whereas FHM3 is caused by mutations in SCN1A, the gene encoding the neuronal CNS specific Na+ channel Nav1.1 [1, 2]
Electrophysiological investigation of 5 uncharacterized FHM3 mutations We introduced the following 5 FMH3 associated mutations into our optimized SCN1A expression plasmid: Q1489H and F1499 L were found in families in which FHM was associated with elicited repetitive daily blindness [36] (F1499 L is a recurrent mutation [37]); I1498M and F1661 L were found in patients with pure hemiplegic migraine [38]; M1500 V was detected by screening a cohort of patients with migraine with aura [39]

Summary

Introduction

Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Familial hemiplegic migraine (FHM) is a severe form of hereditary autosomal dominant migraine with aura caused by mutations in three different genes encoding neuronal or glial ion transporting membrane proteins. The fact that all forms of FHM are associated with ion transporting neuronal/glial specific proteins hints to a “neuronal origin” of FHM and to a disturbance of ionic homeostasis at the basis of the disease In agreement with this general assumption, the phenomenon of cortical spreading depression (CSD), which is characterized by a wave of K+ accumulation and generalized neuronal depolarization, has been proposed to be an essential event in migraine with aura [1]. Some FHM3 mutations result in reduced expression levels in heterologous expression systems [8, 10, 13, 14] For these variants, the exact functional impact in patients cannot be fully predicted, even though an overall gain of function is most likely [10]. It appears extremely important to extend the functional investigation to all known FHM3-linked mutations to arrive at a complete picture

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