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

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Sci. Signal.  30 Jun 2015:
Vol. 8, Issue 383, pp. ra65
DOI: 10.1126/scisignal.aaa0354

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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, 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.

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