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Nat Commun. 2017 Nov 24;8(1):1776. doi: 10.1038/s41467-017-01749-0.

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

Heubl M1,2,3, Zhang J4,5,6, Pressey JC1,2,3, Al Awabdh S1,2,3, Renner M1,2,3, Gomez-Castro F1,2,3, Moutkine I1,2,3, Eugène E1,2,3, Russeau M1,2,3, Kahle KT6, Poncer JC1,2,3, Lévi S7,8,9.

Author information

1
Inserm UMR-S 839, 75005, Paris, France.
2
Université Pierre & Marie Curie, Sorbonne Universités, 75005, Paris, France.
3
Institut du Fer à Moulin, 75005, Paris, France.
4
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland.
5
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, EX4 4PS, UK.
6
Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA.
7
Inserm UMR-S 839, 75005, Paris, France. sabine.levi@inserm.fr.
8
Université Pierre & Marie Curie, Sorbonne Universités, 75005, Paris, France. sabine.levi@inserm.fr.
9
Institut du Fer à Moulin, 75005, Paris, France. sabine.levi@inserm.fr.

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.

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