Inhibition Gets a New KAR Smell

Ionotropic and metabotropic kainate receptor signaling regulates Cl⁻ homeostasis and GABAergic inhibition Garand D, Mahadevan V, Woodin MA. J Physiol. 2018. doi:10.1113/JP276901 Potassium chloride cotransporter 2 (KCC2) plays a critical role in the regulation of chloride (Cl⁻) homeostasis within mature neurons. The KCC2 is a secondarily active transporter that extrudes Cl⁻ from the neuron, which maintains a low intracellular Cl⁻concentration [Cl⁻]. This results in a hyperpolarized reversal potential of GABA (E_GABA), which is required for fast synaptic inhibition in the mature central nervous system. Potassium chloride cotransporter 2 also plays a structural role in dendritic spines and at excitatory synapses and interacts with “excitatory” proteins, including the GluK2 subunit of kainate receptors (KARs). Kainate receptors are glutamate receptors that display both ionotropic and metabotropic signaling. We show that activating KARs in the hippocampus hyperpolarizes E_GABA, thus strengthening inhibition. This hyperpolarization occurs via both ionotropic and metabotropic KAR signaling in the CA3 region, whereas it is absent in the GluK1/2^−/− mouse, and is independent of zinc release from mossy fiber terminals. The metabotropic signaling mechanism is dependent on KCC2, although the ionotropic signaling mechanism produces a hyperpolarization of E_GABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR:KCC2 complex may play an important role in excitatory:inhibitory balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signaling can regulate inhibition via multiple mechanisms. Activation of kainate-type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during periods of strong glutamatergic activity.