Regulation of voltage-gated sodium channel expression, control of excitability and implications for seizure generation

Voltage-gated Na (Na_v) channels are key regulators of neuronal excitability. The mammalian genome encodes multiple Na_vs, but reported channel kinetics greatly exceeds gene number. Recent studies have identified a range of post-transcriptional modifications that, combined, are sufficient to generate diversity in channel kinetics and expression level. These mechanisms include RNA-editing, alternative splicing, translational regulation and protein modification. Pharmacological block of Na_v is a proven clinical approach to treat human epilepsy, but is now generally accepted to be exhausted for the development of next-generation antiepileptics. The molecular components that mediate post-transcriptional modification may, therefore, provide alternate targets for drug design and recent large-scale screens in Drosophila validate this approach.