Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity
Bekir Altas, H. Rhee, Anes Ju, Hugo Cruces Solís, Samir Karaca, Jan Winchenbach, Oykum Kaplan‐Arabaci, Manuela Schwark, Mateusz C. Ambrozkiewicz, 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, Mišo Mitkovski, Livia de Hoz, Alexandros Poulopoulos, Henning Urlaub, Olaf Jahn, Gesine Saher, Nils Brose, JeongSeop Rhee, Hiroshi Kawabe
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.