| The main excitatory neurotransmitter in the mammalian brain is glutamate, and glutamate acts on three classes of ionotropic receptors, AMPA, NMDA, and kainate type glutamate receptors. While the role of AMPA and NMDA receptors in the brain is well understood, the physiological function of kainate receptors (KAR) is unclear, due to a general lack in the understanding of KAR properties in the brain.;Endogenous KAR display several properties that are unique for this family of glutamate receptors. These unique properties cannot be observed after heterologous expression, and it is unknown how they are mediated in vivo. Specifically, the distribution of high-affinity kainate binding sites in the brain and the unusual, slow gating kinetics of synaptic KAR have been described for many years, but the underlying molecular mechanisms are not understood. In addition, it is unclear if KAR are localized pre- or postsynaptically in the brain, and it is unknown which part of the KAR complex might mediate synaptic localization.;Here we find that Neto1 is an auxiliary subunit of KAR in vivo that mediates both the distribution of high-affinity kainate binding sites and the slow gating kinetics of synaptic KAR in the hippocampus. The effect of Neto1 is purely due to modulation of channel properties, and does not mediate expression or localization of KAR. Neto2 shows similar effects then Neto1 in overexpression systems, but is distributed differently in the brain. Furthermore, we describe a postsynaptic distribution of KAR at mossy fiber-granule cell synapses in the cerebellum, and we show that this localization depends on the C-terminus of the low-affinity subunit GluK2.;Together, our data suggest that the physiological function of KAR depends on a family of auxiliary subunits, Neto1 and Neto2, and that KAR contribute to postsynaptic excitatory neurotransmission in certain brain areas. These results will help to better define the role of KAR in the brain, and their contribution to neurological disorders. |
