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The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2019

Open Access 01-12-2019 | Migraine | Research article

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

Authors: R. Barbieri, S. Bertelli, M. Pusch, P. Gavazzo

Published in: The Journal of Headache and Pain | Issue 1/2019

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Abstract

Background

Familial 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.

Methods

To 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.

Results

With 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.

Conclusion

In conclusion, late Na+ current blockers appear a promising specific pharmacological treatment of FHM3.
Appendix
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Metadata
Title
Late sodium current blocker GS967 inhibits persistent currents induced by familial hemiplegic migraine type 3 mutations of the SCN1A gene
Authors
R. Barbieri
S. Bertelli
M. Pusch
P. Gavazzo
Publication date
01-12-2019
Publisher
Springer Milan
Keyword
Migraine
Published in
The Journal of Headache and Pain / Issue 1/2019
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-019-1056-2

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