title: Regulation of membrane excitability: a convergence on voltage-gated sodium conductance.
abstract: The voltage-gated sodium channel (Nav) plays a key role in regulation of neuronal excitability. Aberrant regulation of Nav expression and/or function can result in an imbalance in neuronal activity which can progress to epilepsy. Regulation of Nav 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 Navs. By contrast, the genome of the fruitfly, Drosophila melanogaster, contains just one Nav 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 (INaP). Splicing by Pasilla, an identified RNA splicing factor, alters INaP magnitude as part of an activity-dependent mechanism. Enhanced INaP 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 Navs and, moreover, mouse gene knockouts display seizure-like behaviour.Expression level of Navs 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 (INa) density in neurons. Pum2-deficient mice exhibit spontaneous EEG abnormalities. Taken together, aberrant regulation of Nav 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 Navs should provide new leads to treat epilepsy.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, UK.
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Lin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Baines
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D006706:Homeostasis; D015640:Ion Channel Gating; D008954:Models, Biological; D008969:Molecular Sequence Data; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels