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Neuronal chloride regulation via KCC2 is modulated through a GABAB receptor protein complex

Research output: Contribution to journalArticle

Rebecca Wright, Sarah E Newey, Andrei Ilie, Winnie Wefelmeyer, Joseph V Raimondo, Rachel Ginham, R A Jeffrey Mcllhinney, Colin J Akerman

Original languageEnglish
JournalJournal of Neuroscience
DOIs
Publication statusPublished - 27 Apr 2017

King's Authors

Abstract

GABAB receptors are G-protein coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signalling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride permeable ionotropic GABAA receptor in mature neurons. Using biochemical, molecular and functional studies in rodent hippocampus, we show that activation of GABAB receptors results in a decrease in KCC2 function, which is associated with a reduction in the protein at the cell surface. These findings reveal a novel 'crosstalk' between the GABA receptor systems, which can be recruited under conditions of high GABA release and which could be important for the regulation of inhibitory synaptic transmission.SIGNIFICANCE STATEMENTSynaptic inhibition in the brain is mediated by ionotropic GABAA receptors (GABAARs) and metabotropic GABAB receptors (GABABRs). To fully appreciate the function and regulation of these neurotransmitter receptors, we must understand their interactions with other proteins. We describe a novel association between the GABABR and the potassium-chloride cotransporter protein, KCC2. This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. We demonstrate that GABABR activation can regulate KCC2 at the cell surface, in a manner that alters intracellular chloride and the reversal potential for the GABAAR. Our data therefore supports an additional mechanism by which GABABRs are able to modulate fast synaptic inhibition.

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