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

doi:10.1038/s41467-017-01749-0

GABA_A 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)

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Abstract

The K⁺-Cl^- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABA_A 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 GABA_A receptor (GABA_AR)-mediated transmission in mature hippocampal neurons. Enhancing GABA_AR-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 GABA_AR activity.

Original language	English
Article number	1776
Pages (from-to)	1-17
Number of pages	17
Journal	Nature Communications
Volume	8
Issue number	1
Early online date	24 Nov 2017
DOIs	https://doi.org/10.1038/s41467-017-01749-0
Publication status	Published - 1 Dec 2017

Keywords

Neurophysiology
Neurotransmitters
Transporters in the nervous system

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Cite this

Heubl, M., Zhang, J., Pressey, J. C., Al Awabdh, S., Renner, M., Gomez-Castro, F., Moutkine, I., Eugène, E., Russeau, M., Kahle, K. T., Poncer, J. C., & Lévi, S. (2017). GABA_A receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl^--sensitive WNK1 kinase. Nature Communications, 8(1), 1-17. Article 1776. https://doi.org/10.1038/s41467-017-01749-0

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title = "GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl--sensitive WNK1 kinase",

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.",

keywords = "Neurophysiology, Neurotransmitters, Transporters in the nervous system",

author = "Martin Heubl and Jinwei Zhang and Pressey, {Jessica C.} and {Al Awabdh}, Sana and Marianne Renner and Ferran Gomez-Castro and Imane Moutkine and Emmanuel Eug{\`e}ne and Marion Russeau and Kahle, {Kristopher T.} and Poncer, {Jean Christophe} and Sabine L{\'e}vi",

note = "This work was supported in part by Inserm, Sorbonne Universit{\'e}-UPMC, as well as the Fondation pour la Recherche M{\'e}dicale (Equipe FRM DEQ20140329539 to J.C.P.), the Human Frontier Science Program (RGP0022/2013 to J.C.P.) and the Fondation pour la Recherche sur le Cerveau (to S.L.). Equipment at the IFM was also supported by DIM NeRF from R{\'e}gion Ile-de-France and by the FRC/Rotary {\textquoteleft}Espoir en t{\^e}te{\textquoteright}. M.H. was the recipient of a doctoral fellowship from the Universit{\'e} Pierre and Marie Curie, as well as from Bio-Psy Laboratory of excellence. K.T.K. is supported by the National Institutes of Health, the Simons Foundation, and the March of Dimes Foundation Basil O{\textquoteright}Connor Award. The Poncer/L{\'e}vi lab is affiliated with the Paris School of Neuroscience (ENP) and the Bio-Psy Laboratory of excellence.",

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AU - Heubl, Martin

AU - Zhang, Jinwei

AU - Pressey, Jessica C.

AU - Al Awabdh, Sana

AU - Renner, Marianne

AU - Gomez-Castro, Ferran

AU - Moutkine, Imane

AU - Eugène, Emmanuel

AU - Russeau, Marion

AU - Kahle, Kristopher T.

AU - Poncer, Jean Christophe

AU - Lévi, Sabine

N1 - This work was supported in part by Inserm, Sorbonne Université-UPMC, as well as the Fondation pour la Recherche Médicale (Equipe FRM DEQ20140329539 to J.C.P.), the Human Frontier Science Program (RGP0022/2013 to J.C.P.) and the Fondation pour la Recherche sur le Cerveau (to S.L.). Equipment at the IFM was also supported by DIM NeRF from Région Ile-de-France and by the FRC/Rotary ‘Espoir en tête’. M.H. was the recipient of a doctoral fellowship from the Université Pierre and Marie Curie, as well as from Bio-Psy Laboratory of excellence. K.T.K. is supported by the National Institutes of Health, the Simons Foundation, and the March of Dimes Foundation Basil O’Connor Award. The Poncer/Lévi lab is affiliated with the Paris School of Neuroscience (ENP) and the Bio-Psy Laboratory of excellence.

PY - 2017/12/1

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N2 - 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.

AB - 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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