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GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase

Author

Listed:
  • Martin Heubl

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Jinwei Zhang

    (MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee
    University of Exeter Medical School, Hatherly Laboratory
    Pediatrics, and Cellular & Molecular Physiology, NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine)

  • Jessica C. Pressey

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Sana Al Awabdh

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Marianne Renner

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Ferran Gomez-Castro

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Imane Moutkine

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Emmanuel Eugène

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Marion Russeau

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Kristopher T. Kahle

    (Pediatrics, and Cellular & Molecular Physiology, NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine)

  • Jean Christophe Poncer

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

  • Sabine Lévi

    (Inserm UMR-S 839
    Sorbonne Universités
    Institut du Fer à Moulin)

Abstract

The K+–Cl− co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl−]i. KCC2 undergoes activity-dependent regulation in both physiological and pathological conditions. The regulation of KCC2 by synaptic excitation is well documented; however, whether the transporter is regulated by synaptic inhibition is unknown. Here we report a mechanism of KCC2 regulation by GABAA receptor (GABAAR)-mediated transmission in mature hippocampal neurons. Enhancing GABAAR-mediated inhibition confines KCC2 to the plasma membrane, while antagonizing inhibition reduces KCC2 surface expression by increasing the lateral diffusion and endocytosis of the transporter. This mechanism utilizes Cl− as an intracellular secondary messenger and is dependent on phosphorylation of KCC2 at threonines 906 and 1007 by the Cl−-sensing kinase WNK1. We propose this mechanism contributes to the homeostasis of synaptic inhibition by rapidly adjusting neuronal [Cl−]i to GABAAR activity.

Suggested Citation

  • Martin Heubl & Jinwei Zhang & Jessica C. Pressey & Sana Al Awabdh & Marianne Renner & Ferran Gomez-Castro & Imane Moutkine & Emmanuel Eugène & Marion Russeau & Kristopher T. Kahle & Jean Christophe Po, 2017. "GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01749-0
    DOI: 10.1038/s41467-017-01749-0
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    Cited by:

    1. Enrico Pracucci & Robert T. Graham & Laura Alberio & Gabriele Nardi & Olga Cozzolino & Vinoshene Pillai & Giacomo Pasquini & Luciano Saieva & Darren Walsh & Silvia Landi & Jinwei Zhang & Andrew J. Tre, 2023. "Daily rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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