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Immature neurons need WNK1-dependent phosphorylation of KCC2 to prevent a premature switch in the Cl− gradient and the effect of GABA. Keeping immature neurons excited After birth, signaling by the neurotransmitter GABA in the brain switches from excitatory to inhibitory. GABA mediates both the excitatory and inhibitory responses by binding to ligand-gated ion channels that conduct Cl−. Whether opening these channels triggers hyperpolarization (inhibition) or depolarization (excitation) depends on the concentration of Cl− in neurons. Friedel et al. identified phosphorylation events in the K+-Cl− cotransporter KCC2, which depended on the activity of the kinase WNK1, inhibited KCC2 activity, and contributed to the depolarizing effect of GABA-mediated signaling in immature rat neurons by maintaining high internal Cl− concentration. This regulatory mechanism has implications for the normal developmental excitatory-to-inhibitory GABA switch and neurodevelopmental diseases, such as autism, epilepsy, and spasticity. 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.

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