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Gephyrin interacts with the K-Cl co-transporter KCC2 to regulate its surface expression and function in cortical neurons

ABSTRACT: The K+-Cl- co-transporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes the strength and polarity of GABAA receptor-mediated transmission. Besides 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 submembrane actin cytoskeleton via 4.1N is known to control its anchoring in the vicinity of glutamatergic synapses on dendritic spines. However, the molecular determinants of KCC2 clustering near GABAergic synapses remain unknown. Here, we use proteomics to identify novel KCC2 interacting proteins in adult rat cortex. We identify 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 brain extracts. We show that gephyrin stabilizes plasmalemmal KCC2 and promotes its clustering, notably 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain, Neocortex

SUBMITTER: Functional Proteomics Platform FPP

LAB HEAD: Jean- Christophe Poncer

PROVIDER: PXD022412 | Pride | 2021-11-29

REPOSITORIES: Pride

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