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.