Nedd4-2 (NEDD4L) controls intracellular Na⁺-mediated activity of voltage-gated sodium channels in primary cortical neurons

Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Na_vs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Na_vs. However, the conditions under which Nedd4-2 mediates native Na_v regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Na_vs specifically in response to elevated intracellular Na⁺, but does not affect steady-state Na_v activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Na_v activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Na_vs in the central nervous system.