Regulation of membrane excitability: a convergence on voltage-gated sodium conductance

The voltage-gated sodium channel (Na(v)) plays a key role in regulation of neuronal excitability. Aberrant regulation of Na(v) expression and/or function can result in an imbalance in neuronal activity which can progress to epilepsy. Regulation of Na(v) activity is achieved by coordination of a multitude of mechanisms including RNA alternative splicing and translational repression. Understanding of these regulatory mechanisms is complicated by extensive genetic redundancy: the mammalian genome encodes ten Na(v)s. By contrast, the genome of the fruitfly, Drosophila melanogaster, contains just one Na(v) homologue, encoded by paralytic (DmNa (v)). Analysis of splicing in DmNa (v) shows variants exhibit distinct gating properties including varying magnitudes of persistent sodium current (I(NaP)). Splicing by Pasilla, an identified RNA splicing factor, alters I(NaP) magnitude as part of an activity-dependent mechanism. Enhanced I(NaP) promotes membrane hyperexcitability that is associated with seizure-like behaviour in Drosophila. Nova-2, a mammalian Pasilla homologue, has also been linked to splicing of Na(v)s and, moreover, mouse gene knockouts display seizure-like behaviour. Expression level of Na(v)s is also regulated through a mechanism of translational repression in both flies and mammals. The translational repressor Pumilio (Pum) can bind to Na (v) transcripts and repress the normal process of translation, thus regulating sodium current (I(Na)) density in neurons. Pum2-deficient mice exhibit spontaneous EEG abnormalities. Taken together, aberrant regulation of Na(v) function and/or expression is often epileptogenic. As such, a better understanding of regulation of membrane excitability through RNA alternative splicing and translational repression of Na(v)s should provide new leads to treat epilepsy.