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

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 Poncer and Sabine Lévi ()
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Martin Heubl: Inserm UMR-S 839
Jinwei Zhang: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee
Jessica C. Pressey: Inserm UMR-S 839
Sana Al Awabdh: Inserm UMR-S 839
Marianne Renner: Inserm UMR-S 839
Ferran Gomez-Castro: Inserm UMR-S 839
Imane Moutkine: Inserm UMR-S 839
Emmanuel Eugène: Inserm UMR-S 839
Marion Russeau: Inserm UMR-S 839
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
Sabine Lévi: Inserm UMR-S 839

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01749-0

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