Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states

Katharina L. Dürr, Lei Chen, Richard A. Stein, Rita De Zorzi, I. Mihaela Folea, Thomas Walz, Hassane S. McHaourab, Eric Gouaux

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs to neurotransmission, little is known about the structures and dynamics of intact receptors in distinct functional states. Here, we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with partial agonists and a positive allosteric modulator, and in a desensitized/closed state in complex with fluorowilliardiine. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryoelectron microscopy studies. We show how agonist binding modulates the conformation of the ligand-binding domain "layer" of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of the amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation, and desensitization in AMPA iGluRs.

Original languageEnglish (US)
Pages (from-to)778-792
Number of pages15
JournalCell
Volume158
Issue number4
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dürr, K. L., Chen, L., Stein, R. A., De Zorzi, R., Folea, I. M., Walz, T., McHaourab, H. S., & Gouaux, E. (2014). Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell, 158(4), 778-792. https://doi.org/10.1016/j.cell.2014.07.023