Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Edward C. Twomey, Maria V. Yelshanskaya, Alexander A. Vassilevski, Alexander I. Sobolevsky

Research output: Contribution to journalArticlepeer-review

Abstract

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. Calcium-permeable AMPA receptors (CP-AMPARs) are strongly implicated in neurological disorders. Twomey et al. uncover the structural bases of CP-AMPAR channel block by toxins and their synthetic analogs, providing a foundation for the design of new therapeutic agents.

Original languageEnglish (US)
Pages (from-to)956-968.e4
JournalNeuron
Volume99
Issue number5
DOIs
StatePublished - Sep 5 2018
Externally publishedYes

Keywords

  • AMPA receptors
  • cryoelectron microscopy
  • drug development
  • glutamate receptors
  • ion channel block
  • ion channel structure
  • ion channels
  • ionotropic glutamate receptors
  • neurodegeneration
  • toxins

ASJC Scopus subject areas

  • Neuroscience(all)

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