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

Perrine Friedel, Kristopher T. Kahle (Lead / Corresponding author), Jinwei Zhang, Nicholas Hertz, Lucie I. Pisella, Emmanuelle Buhler, Fabienne Schaller, Jingjing Duan, Arjun R. Khanna, Paul N. Bishop, Kevan M. Shokat, Igor Medina (Lead / Corresponding author)

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Abstract

Activation of Cl--permeable g-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, Thr906 and Thr1007. Phosphorylation of both Thr906 and Thr1007 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.

Original languageEnglish
Article numberra65
Number of pages16
JournalScience Signaling
Volume8
Issue number383
DOIs
Publication statusPublished - 30 Jun 2015

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    Friedel, P., Kahle, K. T., Zhang, J., Hertz, N., Pisella, L. I., Buhler, E., Schaller, F., Duan, J., Khanna, A. R., Bishop, P. N., Shokat, K. M., & Medina, I. (2015). WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Science Signaling, 8(383), [ra65]. https://doi.org/10.1126/scisignal.aaa0354, https://doi.org/10.1126/scisignal.aaa0354