GABA A receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl - -sensitive WNK1 kinase.

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 _A R)-mediated transmission in mature hippocampal neurons. Enhancing GABA _A R-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 _A R activity.