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

Nat Commun. 2017 Nov 24;8(1):1776. doi: 10.1038/s41467-017-01749-0.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Chlorides / metabolism*
  • Endocytosis
  • Hippocampus / cytology
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / enzymology
  • Neurons / metabolism
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Signal Transduction
  • Symporters / genetics
  • Symporters / metabolism*
  • Synaptic Transmission
  • WNK Lysine-Deficient Protein Kinase 1 / genetics
  • WNK Lysine-Deficient Protein Kinase 1 / metabolism*

Substances

  • Chlorides
  • Receptors, GABA-A
  • Symporters
  • potassium-chloride symporters
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse