期刊
JOURNAL OF NEUROSCIENCE
卷 42, 期 2, 页码 166-182出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2926-20.2021
关键词
cerebral cortex; chloride; GABA transmission; KCC2; proteomics; synaptic transmission
资金
- Fondation pour la Recherche Medicale [DEQ20140329539]
- ERANET-Neuron (Agence Nationale de la Recherche)
- Fondation Francaise pour la Recherche sur l'Epilepsie-Federation pour la Recherche sur le Cerveau
- Sorbonne University
KCC2, a neuron-specific chloride extruder, regulates the strength and polarity of GABAA receptor-mediated transmission and also plays a role in spinogenesis and excitatory synaptic function. The study identifies gephyrin as a novel anchoring molecule for KCC2 that stabilizes its plasma membrane expression and promotes its clustering near GABAergic synapses.
The K1-Cl- cotransporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes the strength and polarity of GABAA receptor-mediated transmission. In addition to its canonical ion transport function, KCC2 also regulates spinogenesis and excitatory synaptic function through interaction with a variety of molecular partners. KCC2 is enriched in the vicinity of both glutamatergic and GABAergic synapses, the activity of which in turn regulates its membrane stability and function. KCC2 interaction with the submembrane actin cytoskeleton via 4.1N is known to control its anchoring near glutamatergic synapses on dendritic spines. However, the molecular determinants of KCC2 clustering near GABAergic synapses remain unknown. Here, we used proteomics to identify novel KCC2 interacting proteins in the adult rat neocortex. We identified both known and novel candidate KCC2 partners, including some involved in neuronal development and synaptic transmission. These include gephyrin, the main scaffolding molecule at GABAergic synapses. Gephyrin interaction with endogenous KCC2 was confirmed by immunoprecipitation from rat neocortical extracts. We showed that gephyrin stabilizes plasmalemmal KCC2 and promotes its clustering in hippocampal neurons, mostly but not exclusively near GABAergic synapses, thereby controlling KCC2-mediated chloride extrusion. This study identifies gephyrin as a novel KCC2 anchoring molecule that regulates its membrane expression and function in cortical neurons.
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