PubMed 20420834

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1.3 , Nav1.7

Title: A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons.

Authors: Mark Estacion, Andreas Gasser, Sulayman D Dib-Hajj, Stephen G Waxman

Journal, date & volume: Exp. Neurol., 2010 Aug , 224, 362-8

PubMed link:

Voltage-gated sodium channelopathies underlie many excitability disorders. Genes SCN1A, SCN2A and SCN9A, which encode pore-forming alpha-subunits Na(V)1.1, Na(V)1.2 and Na(V)1.7, are clustered on human chromosome 2, and mutations in these genes have been shown to underlie epilepsy, migraine, and somatic pain disorders. SCN3A, the gene which encodes Na(V)1.3, is part of this cluster, but until recently was not associated with any mutation. A charge-neutralizing mutation, K345Q, in the Na(V)1.3 DI/S5-6 linker has recently been identified in a patient with cryptogenic partial epilepsy. Pathogenicity of the Na(V)1.3/K354Q mutation has been inferred from the conservation of this residue in all sodium channels and its absence from control alleles, but functional analysis has been limited to the corresponding substitution in the cardiac muscle sodium channel Na(V)1.5. Since identical mutations may produce different effects within different sodium channel isoforms, we assessed the K354Q mutation within its native Na(V)1.3 channel and studied the effect of the mutant Na(V)1.3/K354Q channels on hippocampal neuron excitability. We show here that the K354Q mutation enhances the persistent and ramp currents of Na(V)1.3, reduces current threshold and produces spontaneous firing and paroxysmal depolarizing shift-like complexes in hippocampal neurons. Our data provide a pathophysiological basis for the pathogenicity of the first epilepsy-linked mutation within Na(V)1.3 channels and hippocampal neurons.