PNNL

Abstract

Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions of the mammalian brain. AMPA receptors are tetrameric assemblies composed of four subunits, GluA1-4. Despite decades of study, the subunit composition, subunit arrangement, and molecular structure of native AMPA receptors remains unknown. Here we elucidate the structure of 10 distinct native AMPA receptor complexes by single particle cryo-EM. We find that receptor subunits are arranged non-stochastically, with the GluA2 subunit preferentially occupying the B/D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Density maps define the structure for previously unseen linking peptides between the ligand binding and transmembrane domains, showing how neurotransmitter binding is coupled to ion channel gating.