| First Author | Altas B | Year | 2024 |
| Journal | J Cell Biol | Volume | 223 |
| Issue | 1 | PubMed ID | 38032389 |
| Mgi Jnum | J:343429 | Mgi Id | MGI:7563806 |
| Doi | 10.1083/jcb.201902050 | Citation | Altas B, et al. (2024) Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity. J Cell Biol 223(1) |
| abstractText | 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 gamma-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. |
