Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity-Reference-Cited by-同舟云学术

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

Published:2023-11-30 Issue:1 Volume:223 Page:
ISSN:0021-9525
Container-title:Journal of Cell Biology
language:en
Short-container-title:

Author:

Altas Bekir¹²³⁴^ORCID,Rhee Hong-Jun¹^ORCID,Ju Anes¹³^ORCID,Solís Hugo Cruces¹²⁵,Karaca Samir²⁶^ORCID,Winchenbach Jan³⁵^ORCID,Kaplan-Arabaci Oykum¹⁷^ORCID,Schwark Manuela¹^ORCID,Ambrozkiewicz Mateusz C.¹²⁸⁹^ORCID,Lee ChungKu¹^ORCID,Spieth Lena⁵^ORCID,Wieser Georg L.¹⁰^ORCID,Chaugule Viduth K.¹¹^ORCID,Majoul Irina¹²^ORCID,Hassan Mohamed A.¹¹³^ORCID,Goel Rashi¹^ORCID,Wojcik Sonja M.¹^ORCID,Koganezawa Noriko¹⁴^ORCID,Hanamura Kenji¹⁴^ORCID,Rotin Daniela¹⁵^ORCID,Pichler Andrea¹¹^ORCID,Mitkovski Miso¹⁰^ORCID,de Hoz Livia⁵^ORCID,Poulopoulos Alexandros⁴^ORCID,Urlaub Henning⁶¹⁶¹⁷^ORCID,Jahn Olaf¹⁸¹⁹^ORCID,Saher Gesine⁵^ORCID,Brose Nils¹^ORCID,Rhee JeongSeop¹,Kawabe Hiroshi¹¹⁴²⁰²¹^ORCID

Affiliation:

1. Max Planck Institute for Multidisciplinary Sciences 1 Department of Molecular Neurobiology, , Göttingen, Germany

2. International Max Planck Research School and the Göttingen Graduate School for Neurosciences, Biophysics and Molecular Biosciences 2 , Göttingen, Germany

3. The Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, PhD Program Systems Neuroscience, University of Göttingen 3 , Göttingen, Germany

4. University of Maryland School of Medicine 4 Department of Pharmacology and Program in Neuroscience, , Baltimore, MD, USA

5. Max Planck Institute for Multidisciplinary Sciences 5 Department of Neurogenetics, , Göttingen, Germany

6. Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences 6 , Göttingen, Germany

7. The Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, PhD Program Molecular Physiology of the Brain, University of Göttingen 7 , Göttingen, Germany

8. Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin 8 , , Berlin, Germany

9. Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health 8 , , Berlin, Germany

10. City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences 9 , Göttingen, Germany

11. Max Planck Institute of Immunobiology and Epigenetics 10 Department of Epigenetics, , Freiburg, Germany

12. University of Lübeck 11 Institute of Biology, Center for Structural and Cell Biology in Medicine, , Lübeck, Germany

13. Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City) 12 Protein Research Department, , New Borg El-Arab City, Egypt

14. Gunma University Graduate School of Medicine 13 Department of Pharmacology, , Maebashi, Japan

15. The Hospital for Sick Children and University of Toronto 14 , Toronto, Canada

16. Bioanalytics, Institute for Clinical Chemistry, University Medical Center Göttingen 15 , Göttingen, Germany

17. Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen 16 , Göttingen, Germany

18. Neuroproteomics Group, Max Planck Institute for Multidisciplinary Sciences 17 Department of Molecular Neurobiology, , Göttingen, Germany

19. Translational Neuroproteomics Group, University Medical Center Göttingen 18 Department of Psychiatry and Psychotherapy, , Göttingen, Germany

20. Kobe University Graduate School of Medicine 19 Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, , Kobe, Japan

21. Foundation for Biomedical Research and Innovation at Kobe 20 Department of Gerontology, Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, , Kobe, Japan

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.

Funder

Canadian Institutes of Health Research

German Research Foundation

Fritz Thyssen Foundation

Japan Society for the Promotion of Science

Mother and Child Health Foundation

Ohsumi Frontier Science Foundation

Takeda Science Foundation

Daiichi Sankyo Foundation of Life Science

Terumo Foundation for Life Sciences

Naito Foundation

Uehara Memorial Foundation