Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM

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 and modulator complex harbors an ion-permeable channel gate, providing the first view of an activated AMPA receptor. [Display omitted] •Agonist-bound complexes illuminate mechanisms of activation and desensitization•Partially open channel gate and complete pore structure defined in active states•TARPs act as molecular “buoys” and prevent LBD compression toward membrane•TARPs encircle LBDs and reduce conformational heterogeneity upon desensitization Cryo-EM reconstructions of an AMPA receptor-TARP complex illuminate receptor activation and desensitization.