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Sci Signal. 2015 Jun 30;8(383):ra65. doi: 10.1126/scisignal.aaa0354.

WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons.

Author information

1
Institut de Neurobiologie de la Méditerranée (INMED), INSERM Unité 901, 13273 Marseille, France. Aix-Marseille Université, UMR 901, 13273 Marseille, France.
2
Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. kkahle@enders.tch.harvard.edu igor.medyna@inserm.fr.
3
UK Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
4
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143-0450, USA.
5
Aix-Marseille Université, UMR 901, 13273 Marseille, France. Plateforme Post-Génomique, INMED, 13273 Marseille, France.
6
Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
7
School of Biochemistry, University of Bristol, Bristol BS8 1TH, UK.
8
Institut de Neurobiologie de la Méditerranée (INMED), INSERM Unité 901, 13273 Marseille, France. Aix-Marseille Université, UMR 901, 13273 Marseille, France. kkahle@enders.tch.harvard.edu igor.medyna@inserm.fr.

Abstract

Activation of Cl(-)-permeable γ-aminobutyric acid type A (GABAA) receptors elicits synaptic inhibition in mature neurons but excitation in immature neurons. This developmental "switch" in the GABA function depends on a postnatal decrease in intraneuronal Cl(-) concentration mediated by KCC2, a Cl(-)-extruding K(+)-Cl(-) cotransporter. We showed that the serine-threonine kinase WNK1 [with no lysine (K)] forms a physical complex with KCC2 in the developing mouse brain. Dominant-negative mutation, genetic depletion, or chemical inhibition of WNK1 in immature neurons triggered a hyperpolarizing shift in GABA activity by enhancing KCC2-mediated Cl(-) extrusion. This increase in KCC2 activity resulted from reduced inhibitory phosphorylation of KCC2 at two C-terminal threonines, Thr(906) and Thr(1007). Phosphorylation of both Thr(906) and Thr(1007) was increased in immature versus mature neurons. Together, these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1-regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence.

PMID:
26126716
DOI:
10.1126/scisignal.aaa0354
[Indexed for MEDLINE]

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