Neuronal Chloride Regulation via KCC2 Is Modulated through a GABABReceptor Protein Complex.
Wright R., Newey SE., Ilie A., Wefelmeyer W., Raimondo JV., Ginham R., Mcllhinney RAJ., Akerman CJ.
GABABreceptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABABreceptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABABreceptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABAAreceptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABABreceptors 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 GABAAreceptors (GABAARs) and metabotropic GABABreceptors (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 support an additional mechanism by which GABABRs are able to modulate fast synaptic inhibition.