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GABA B receptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABA B receptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABA B receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABA A receptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABA B 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 STATEMENT Synaptic inhibition in the brain is mediated by ionotropic GABA A receptors (GABA A Rs) and metabotropic GABA B receptors (GABA B Rs). 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 GABA B R 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 GABA A R. We demonstrate that GABA B R activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABA A R. Our data therefore support an additional mechanism by which GABA B Rs are able to modulate fast synaptic inhibition.

Neuronal Chloride Regulation via KCC2 Is Modulated through a GABABReceptor Protein Complex

Neuronal Chloride Regulation via KCC2 Is Modulated through a GABA_BReceptor Protein Complex