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, Sabine Lévi (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
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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.

Original languageEnglish
Article number1776
Pages (from-to)1-17
Number of pages17
JournalNature Communications
Volume8
Issue number1
Early online date24 Nov 2017
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • Neurophysiology
  • Neurotransmitters
  • Transporters in the nervous system

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