Architecture of fully occupied GluA2 AMPA receptor - TARP complex elucidated by single particle cryo-electron microscopy

Fast excitatory neurotransmission in the mammalian central nervous system is largely carried out by AMPA-sensitive ionotropic glutamate receptors. Localized within the postsynaptic density of glutamatergic spines, AMPA receptors are composed of heterotetrameric receptor assemblies associated with auxiliary subunits, the most common of which are transmembrane AMPA-receptor regulatory proteins (TARPs). The association of TARPs with AMPA receptors modulates the kinetics of receptor gating and pharmacology, as well as trafficking. Here we report the cryo-EM structure of the homomeric GluA2 AMPA receptor saturated with TARP {gamma}2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TM helices. Poised like partially opened hands underneath the two-fold symmetric ligand binding domain (LBD) clamshells, one pair of TARPs are juxtaposed near the LBD dimer interface, while the other pair are near the LBD dimer-dimer interface. The extracellular domains of TARP are positioned to not only modulate LBD clamshell closure, but also to affect conformational rearrangements of the LBD layer associated with receptor activation and desensitization, while the TARP transmembrane (TM) domains buttress the ion channel pore.