Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity
- PMID: 38032389
- PMCID: PMC10689203
- DOI: 10.1083/jcb.201902050
Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity
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.
© 2023 Altas et al.
Conflict of interest statement
Disclosures: The authors declare no competing interests exist.
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References
-
- Albert, T.K., Hanzawa H., Legtenberg Y.I.A., de Ruwe M.J., van den Heuvel F.A.J., Collart M.A., Boelens R., and Timmers H.T.M.. 2002. Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex. EMBO J. 21:355–364. 10.1093/emboj/21.3.355 - DOI - PMC - PubMed
-
- Araque, A., Sanzgiri R.P., Parpura V., and Haydon P.G.. 1998. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J. Neurosci. 18:6822–6829. 10.1523/JNEUROSCI.18-17-06822.1998 - DOI - PMC - PubMed
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