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Cell. 2017 Sep 7;170(6):1234-1246.e14. doi: 10.1016/j.cell.2017.07.045. Epub 2017 Aug 17.

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

Author information

1
Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
2
NIH Center for Macromolecular Modeling and Bioinformatics, Department of Biochemistry, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
3
Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: gouauxe@ohsu.edu.

Abstract

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.

KEYWORDS:

chemical synapse; glutamate receptor; ion channel gating; ligand gated ion channel; membrane protein; neurotransmitter; structural biology; synapse

PMID:
28823560
PMCID:
PMC5621841
DOI:
10.1016/j.cell.2017.07.045
[Indexed for MEDLINE]
Free PMC Article

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