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Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development.

The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. The transmembrane helix of NETO2 is positioned proximal to the selectivity filter and competes with the amphiphilic H1 helix after M4 for interaction with an intracellular cap domain formed by the M1–M2 linkers of the receptor, revealing how rectification is regulated by NETO2. We find that NETO2 accesses only two broad faces of kainate receptors, intermolecularly crosslinking the lower lobe of ATD A/C, the upper lobe of LBD B/D and the lower lobe of LBD A/C, illustrating how NETO2 regulates receptor-gating kinetics. Here we report cryo-electron microscopy structures of homotetrameric GluK2 in complex with NETO2 at inhibited and desensitized states, illustrating variable stoichiometry of GluK2–NETO2 complexes, with one or two NETO2 subunits associating with GluK2. In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins 8, 9, 10, 11.

Glutamate-gated kainate receptors are ubiquitous in the central nervous system of vertebrates, mediate synaptic transmission at the postsynapse and modulate transmitter release at the presynapse 1, 2, 3, 4, 5, 6, 7.