LAUSR

Diversity in ion channel complexes AMPA receptors are glutamate activated ion channels that mediate fast synaptic transmission in the nervous system and play a key role in learning and memory. The receptors are tetramers built from various combinations of four subunits, with functional diversity coming from the range of subunit compositions. Zhao et al. purified native receptors from rat brains and determined the structures of 10 different complexes by cryo–electron microscopy. Certain arrangements of the four subunits are preferred. The structure of a key gating element—a linker between the transmembrane and ligand binding domains—reveals how this receptor may function. Science, this issue p. 355 Overall structure, subunit composition, and spatial configuration are determined for native AMPA receptors in the mammalian brain. 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–GluA4. Despite decades of study, the subunit composition, subunit arrangement, and molecular structure of native AMPA receptors remain unknown. Here we elucidate the structures of 10 distinct native AMPA receptor complexes by single-particle cryo–electron microscopy (cryo-EM). We find that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.