title: Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel.
abstract: Familial hemiplegic migraine (FHM) is an autosomal dominant inherited subtype of severe migraine with aura. Mutations causing FHM (type 3) have been identified in SCN1A, the gene encoding neuronal voltage-gated Na(v)1.1 Na(+) channel alpha subunit, but functional studies have been done using the cardiac Na(v)1.5 isoform, and the observed effects were similar to those of some epileptogenic mutations. We studied the FHM mutation Q1489K by transfecting tsA-201 cells and cultured neurons with human Na(v)1.1. We show that the mutation has effects on the gating properties of the channel that can be consistent with both hyperexcitability and hypoexcitability. Simulation of neuronal firing and long depolarizing pulses mimicking promigraine conditions revealed that the effect of the mutation is a gain of function consistent with increased neuronal firing. However, during high-frequency discharges and long depolarizations, the effect became a loss of function. Recordings of firing of transfected neurons showed higher firing frequency at the beginning of long discharges. This self-limited capacity to induce neuronal hyperexcitability may be a specific characteristic of migraine mutations, able to both trigger the cascade of events that leads to migraine and counteract the development of extreme hyperexcitability typical of epileptic seizures. Thus, we found a possible difference in the functional effects of FHM and familial epilepsy mutations of Nav1.1.
authors.affiliation: Department of Neurophysiopathology, Besta Neurological Institute, 20133 Milan, Italy.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cestèle
authors.forename: Paolo
authors.initials: P
authors.lastname: Scalmani
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Benedetta
authors.initials: B
authors.lastname: Terragni
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005973:Glutamine / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D008239:Lysine / Q000235:genetics; D020325:Migraine with Aura / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels; D005973:Glutamine; D008239:Lysine