Activation and desensitization mechanism of AMPA receptor-TARP complex by cryo-EM
AMPA receptors mediate the majority of 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 altered gating kinetics, receptor pharmacology and pore properties. Here we elucidate full-length GluA2-TARP γ2 complex structures in the presence of the partial agonist kainate or the full agonist quisqualate together with a positive allosteric modulator, and with quisqualate alone. We show how TARPs sculpt the ligand binding domain gating ring, enhancing kainate potency and diminishing the ensemble of desensitized states. The 4 TARPs encircle receptor ion channel, stabilizing M2 helices and pore loops, thus showing how TARPs alter receptor pore properties. Structural and computational analysis suggests the full agonist/modulator complex harbors an ion-permeable channel gate, thus providing the first view of an activated AMPA receptor.
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