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

Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors.

Author information

1
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, NY 10032, USA.
2
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
3
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Oblast 141700, Russia.
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: as4005@cumc.columbia.edu.

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.

KEYWORDS:

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

PMID:
30122377
PMCID:
PMC6181147
[Available on 2019-09-05]
DOI:
10.1016/j.neuron.2018.07.027

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