title: Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons.
abstract: Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Navs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Navs. However, the conditions under which Nedd4-2 mediates native Nav regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Navs specifically in response to elevated intracellular Na(+), but does not affect steady-state Nav activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Nav activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system.
authors.affiliation: *School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4001, Australia.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Ekberg
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Boase
authors.forename: Grigori
authors.initials: G
authors.lastname: Rychkov
authors.forename: Jantina
authors.initials: J
authors.lastname: Manning
authors.forename: Philip
authors.initials: P
authors.lastname: Poronnik
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D004622:Embryo, Mammalian; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D012964:Sodium / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*; D029867:Xenopus Proteins
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D061566:Voltage-Gated Sodium Channels; D029867:Xenopus Proteins; D012964:Sodium; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618482:Nedd4 protein, Xenopus; C000618461:Nedd4l protein, mouse; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases