Modulation of AMPA and kainate receptors by galectins

Abstract

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.