Auxiliary proteins modify the biophysical function and pharmacological properties of ionotropic glutamate receptors and likely are important components of receptor signaling complexes in vivo. NETO1 and NETO2, two closely related CUB domain-containing integral membrane proteins, were identified recently as auxiliary proteins that slowed GluK2a kainate receptor current kinetics without impacting receptor membrane localization. Here we demonstrate that NETO2 profoundly slows the desensitization rate of GluK1 kainate receptors, promotes plasma membrane localization of transfected receptors in heterologous cells and rat hippocampal neurons, and targets GluK1-containing receptors to synapses. Conversely, the closely related protein NETO1 increases the rate of GluK1 receptor desensitization. Incorporation of NETO proteins into kainate receptor signaling complexes therefore extends the temporal range of receptor gating by over an order of magnitude. The presence of these auxiliary proteins could underlie some of the unusual aspects of kainate receptor function in the mammalian CNS.

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N‐glycans covalently attached to integral membrane proteins on neurons act as a reservoir for considerable structural diversity and represent potential sites of modulation by oligosaccharide‐binding proteins known as lectins. We found that galectins, a family of galactose‐binding lectins, act as allosteric modulators of ionotropic glutamate receptors (iGluRs) and engage signaling pathways that lead to alterations in dendritic structure. These proteins could potentially impact synaptic transmission and likely have diverse effects on neuronal signaling in the mammalian CNS.Natural galectins isolated from a marine sponge and the Conger eel, as well as recombinant human galectin‐1, exhibited diverse activity on iGluRs. Several types of receptors, including GluA4 AMPA and GluK2 kainate receptors, responded with slowed desensitization kinetics and increased steady‐state currents. Peak current amplitudes from homomeric GluA1 AMPA and GluK1 kainate receptors were reduced. AMPA and kainate receptors assembled with their respective auxiliary proteins, stargazin and NETO, also were sensitive to allosteric modulation. Galectin modulation of GluK2 receptor function was eliminated by mutation of three extracellular asparagines near the ligand‐binding domain. Hippocampal neurons exposed to galectin‐1 exhibited rapid activation of the MAPK/Erk signaling pathway and longer‐term alterations in neuronal morphology. This spectrum of effects suggests that galectins could impact neuronal function through actions on a variety of signaling pathways. Because they are secreted at high levels in several pathological states, their activity on neurons could potentially exacerbate excitotoxicity.