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

Shanshuang Chen, Yan Zhao, Yuhang Wang, Mrinal Shekhar, Emad Tajkhorshid, Eric Gouaux

Research output: Contribution to journalArticle

37 Citations (Scopus)

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. Cryo-EM reconstructions of an AMPA receptor-TARP complex illuminate receptor activation and desensitization.

Original languageEnglish (US)
JournalCell
DOIs
StateAccepted/In press - 2017

Fingerprint

AMPA Receptors
Chemical activation
Proteins
Quisqualic Acid
Kainic Acid
Ion Channels
Modulators
Post-Synaptic Density
Ports and harbors
Synaptic Transmission
Cations
Glutamic Acid
Brain
Pharmacology
Ions
Ligands
Kinetics

Keywords

  • Chemical synapse
  • Glutamate receptor
  • Ion channel gating
  • Ligand gated ion channel
  • Membrane protein
  • Neurotransmitter
  • Structural biology
  • Synapse

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM. / Chen, Shanshuang; Zhao, Yan; Wang, Yuhang; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric.

In: Cell, 2017.

Research output: Contribution to journalArticle

Chen, Shanshuang ; Zhao, Yan ; Wang, Yuhang ; Shekhar, Mrinal ; Tajkhorshid, Emad ; Gouaux, Eric. / Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM. In: Cell. 2017.
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AU - Tajkhorshid, Emad

AU - Gouaux, Eric

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