RT Journal Article
SR Electronic
T1 Activation and desensitization mechanism of AMPA receptor – TARP complex by cryo-EM
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 158402
DO 10.1101/158402
A1 Shanshuang Chen
A1 Yan Zhao
A1 Yuhang (Steven) Wang
A1 Mrinal Shekhar
A1 Emad Tajkhorshid
A1 Eric Gouaux
YR 2017
UL http://biorxiv.org/content/early/2017/07/01/158402.abstract
AB AMPA receptors mediate fast excitatory neurotransmission in the mammalian brain and transduce the binding of presynaptically released glutamate to the opening of a transmembrane cation channel. Within the postsynaptic density, however, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs), yielding a receptor complex with altered gating kinetics, pharmacology and pore properties. Here we elucidate structures of the GluA2-TARP γ2 complex in the presence of the partial agonist kainate or the full agonist quisqualate together with a positive allosteric modulator, or with quisqualate alone. We show how TARPs sculpt the ligand binding domain gating ring, enhancing kainate potency and diminishing the ensemble of desensitized states. TARPs encircle the receptor ion channel, stabilizing M2 helices and pore loops, illustrating how TARPs alter receptor pore properties. Structural and computational analysis suggests the full agonist/modulator complex harbors an ion-permeable channel gate, providing the first view of an activated AMPA receptor.