Shanshuang Chen, Yan Zhao, Yuhang Wang, Mrinal Shekhar, Emad Tajkhorshid, and
Eric Gouaux.
Activation and desensitization mechanism of AMPA receptor-tarp
complex by cryo-EM.
Cell, 170:1234-1246, 2017.
(PMC: PMC5621841)
CHEN2017-ET
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 2 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 and modulator complex harbors an ion-permeable channel gate,
providing the first
view of an activated AMPA receptor.
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