GABA<sub>A</sub> receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl<sup>-</sup>-sensitive WNK1 kinase.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29176664.
- Also identified by DOI 10.1038/s41467-017-01749-0 and PMC identifier 5701213.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 regulation by GABA<sub>A</sub> receptor (GABA<sub>A</sub>R)-mediated transmission in mature hippocampal neurons. Enhancing GABA<sub>A</sub>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<sup>-</sup> as an intracellular secondary messenger and is dependent on phosphorylation of KCC2 at threonines 906 and 1007 by the Cl<sup>-</sup>-sensing kinase WNK1. We propose this mechanism contributes to the homeostasis of synaptic inhibition by rapidly adjusting neuronal [Cl<sup>-</sup>]<sub>i</sub> to GABA<sub>A</sub>R activity.
Medical subject headings
- Chlorides
- Receptors, GABA-A
- Symporters
- WNK Lysine-Deficient Protein Kinase 1