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

• DOI: 10.1083/jcb.201902050
• Publication Date: 2023-11-30T14:01:26Z
• Authors: Bekir Altas; Hong-Jun Rhee; Anes Ju; Hugo Cruces Solís; Samir Karaca; Jan Winchenbach; Oykum Kaplan-Arabaci; Manuela Schwark; Mateusz C. Ambroz...; ChungKu Lee; Lena Spieth; Georg L. Wieser; Viduth K. Chaugule; Irina Majoul; Mohamed A. Hassan; Rashi Goel; Sonja M. Wojcik; Noriko Koganezawa; Kenji Hanamura; Daniela Rotin; Andrea Pichler; Miso Mitkovski; Livia de Hoz; Alexandros Poulop...; Henning Urlaub; Olaf Jahn; Gesine Saher; Nils Brose; JeongSeop Rhee; Hiroshi Kawabe
• Keywords: NEDD4

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