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

ABSTRACT: The K+-Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA 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 GABAA receptor (GABAAR)-mediated transmission in mature hippocampal neurons. Enhancing GABAAR-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 GABAAR activity.

SUBMITTER: Heubl M 

PROVIDER: S-EPMC5701213 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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GABA<sub>A</sub> receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl<sup>-</sup>-sensitive WNK1 kinase.

Heubl Martin M   Zhang Jinwei J   Pressey Jessica C JC   Al Awabdh Sana S   Renner Marianne M   Gomez-Castro Ferran F   Moutkine Imane I   Eugène Emmanuel E   Russeau Marion M   Kahle Kristopher T KT   Poncer Jean Christophe JC   Lévi Sabine S  

Nature communications 20171124 1

The K<sup>+</sup>-Cl<sup>-</sup> co-transporter KCC2 (SLC12A5) tunes the efficacy of GABA<sub>A</sub> receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl<sup>-</sup>]<sub>i</sub>. 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 regu  ...[more]