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Neurotransmitter-gated ion channels adopt different gating modes to fine-tune signaling at central synapses. At glutamatergic synapses, high and low activity of AMPA receptors (AMPARs) is observed when pore-forming subunits coassemble with or without auxiliary subunits, respectively. Whether a common structural pathway accounts for these different gating modes is unclear. Here, we identify two structural motifs that determine the time course of AMPAR channel activation. A network of electrostatic interactions at the apex of the AMPAR ligand-binding domain (LBD) is essential for gating by pore-forming subunits, whereas a conserved motif on the lower, D2 lobe of the LBD prolongs channel activity when auxiliary subunits are present. Accordingly, channel activity is almost entirely abolished by elimination of the electrostatic network but restored via auxiliary protein interactions at the D2 lobe. In summary, we propose that activation of native AMPAR complexes is coordinated by distinct structural pathways, favored by the association/dissociation of auxiliary subunits.

Original publication

DOI

10.1016/j.neuron.2016.01.038

Type

Journal article

Journal

Neuron

Publication Date

16/03/2016

Volume

89

Pages

1264 - 1276

Keywords

Binding Sites, Crystallography, X-Ray, Electric Stimulation, Glutamic Acid, HEK293 Cells, Humans, Ion Channel Gating, Lithium, Membrane Potentials, Models, Molecular, Mutation, Patch-Clamp Techniques, Protein Structure, Tertiary, Protein Subunits, Receptors, AMPA, Static Electricity, Transfection