Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Neuron. 2018 Sep 5;99(5):956-968.e4. doi: 10.1016/j.neuron.2018.07.027. Epub 2018 Aug 16.


AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.

Keywords: AMPA receptors; cryoelectron microscopy; drug development; glutamate receptors; ion channel block; ion channel structure; ion channels; ionotropic glutamate receptors; neurodegeneration; toxins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Excitatory Amino Acid Antagonists / chemistry*
  • Excitatory Amino Acid Antagonists / metabolism*
  • Excitatory Amino Acid Antagonists / pharmacology
  • HEK293 Cells
  • Humans
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Rats
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / chemistry*
  • Receptors, AMPA / metabolism*
  • Spider Venoms / chemistry
  • Spider Venoms / metabolism
  • Spider Venoms / pharmacology


  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Spider Venoms
  • Calcium