期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01749-0
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资金
- Inserm
- Sorbonne Universite-UPMC
- Fondation pour la Recherche Medicale [Equipe FRM DEQ20140329539]
- Human Frontier Science Program [RGP0022/2013]
- Fondation pour la Recherche sur le Cerveau
- DIM NeRF from Region Ile-de-France
- FRC/Rotary 'Espoir en tete'
- Universite Pierre and Marie Curie
- Bio-Psy Laboratory of excellence
- National Institutes of Health
- Simons Foundation
- March of Dimes Foundation Basil O'Connor Award
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.
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