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

• DOI: 10.1038/s41467-017-01749-0
• Publication Date: 2017-11-20T17:49:10Z
• Authors: Martin Heubl; Jinwei Zhang; Jessica C. Pressey; Sana Al Awabdh; Marianne Renner; Ferran Gomez-Castro; Imane Moutkine; Emmanuel Eugène; Marion Russeau; Kristopher T. Kahle; Jean Christophe P...; Sabine Lévi
• Keywords: Male; 0301 basic medicine; 570; [SDV]Life Sciences [q-bio]; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Science; Neurophysiology; Hippocampus; Synaptic Transmission; Article; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Chlorides; WNK Lysine-Deficient Protein Kinase 1; name=General Biochemistry,Genetics and Molecular Biology; 617; Animals; Phosphorylation; Transporters in the nervous system; Cells, Cultured; Neurons; /dk/atira/pure/subjectarea/asjc/1300/1300; Symporters; Q; Cell Membrane; Neurotransmitters; Receptors, GABA-A; Endocytosis; Rats; Mice, Inbred C57BL; K Cl- Cotransporters; name=General Physics and Astronomy; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; /dk/atira/pure/subjectarea/asjc/3100/3100; name=General Chemistry; /dk/atira/pure/subjectarea/asjc/1600/1600; Signal Transduction

The K+-Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating intraneuronal chloride concentration [Cl-]i. undergoes activity-dependent regulation in both physiological and pathological conditions. synaptic excitation is well documented; however, whether transporter regulated inhibition unknown. Here we report a mechanism receptor (GABAAR)-mediated mature hippocampal neurons. Enhancing GABAAR-mediated confines to plasma membrane, while antagonizing reduces surface expression increasing lateral diffusion endocytosis transporter. This utilizes Cl- as an intracellular secondary messenger dependent on phosphorylation at threonines 906 1007 Cl--sensing kinase WNK1. We propose this contributes homeostasis rapidly adjusting neuronal [Cl-]i GABAAR activity.