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Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant.


Authors: Raffaella Rusconi, Paolo Scalmani, Rita Restano Cassulini, Giulia Giunti, Antonio Gambardella, Silvana Franceschetti, Grazia Annesi, Enzo Wanke, Massimo Mantegazza

Journal, date & volume: J. Neurosci., 2007 Oct 10 , 27, 11037-46

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17928445

Channelpedia reference in: Nav1.1

Abstract
Familial epilepsies are often caused by mutations of voltage-gated Na+ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na(v)1.1 (SCN1A) Na+ channel alpha subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30 degrees C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na+ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.