Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP gamma8
The cryo-EM structure of the GluA1/2 AMPAR heterotetramer in complex with TARP γ8, the main AMPAR complex in the hippocampus, reveals the subunit organization, structural bases of the modulatory properties of γ8 and the molecular details of the ion conducting pore.
Herguedas B, Watson JF, Ho H, Cais O, Garcia-Nafria J, Greger IH.
Science 2019 Apr; 364: eaav9011.
AMPA-type glutamate receptors (AMPARs) mediate excitatory neurotransmission and are central regulators of synaptic plasticity, a molecular mechanism underlying learning and memory. Although AMPARs act predominantly as heteromers, structural studies have focused on homomeric assemblies. Here, we present a cryo-electron microscopy structure of the heteromeric GluA1/2 receptor associated with two transmembrane AMPAR regulatory protein (TARP) gamma8 auxiliary subunits, the principal AMPAR complex at hippocampal synapses. Within the receptor, the core subunits arrange to give the GluA2 subunit dominant control of gating. This structure reveals the geometry of the Q/R site that controls calcium flux, suggests association of TARP-stabilized lipids, and demonstrates that the extracellular loop of gamma8 modulates gating by selectively interacting with the GluA2 ligand-binding domain. Collectively, this structure provides a blueprint for deciphering the signal transduction mechanisms of synaptic AMPARs.
PubMed: 30872532. Doi: 10.1126/science.aav9011. Free PMC article
