Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity

J Cell Biol. 2024 Jan 1;223(1):e201902050. doi: 10.1083/jcb.201902050. Epub 2023 Nov 30.

Abstract

Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of the Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes*
  • Cell Membrane Permeability*
  • Connexin 43* / genetics
  • Epilepsy
  • Humans
  • Mice
  • Mutation, Missense
  • Nedd4 Ubiquitin Protein Ligases* / genetics
  • Potassium Channels, Inwardly Rectifying* / genetics
  • Proteostasis

Substances

  • Connexin 43
  • Kcnj10 (channel)
  • GJA1 protein, mouse
  • Nedd4 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Nedd4 Ubiquitin Protein Ligases

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