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Title | Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors. |
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Journal, issue, pages | Neuron, Vol. 99, Issue 5, Page 956-968.e4, Year 2018 |
Publish date | Sep 5, 2018 |
Authors | Edward C Twomey / Maria V Yelshanskaya / Alexander A Vassilevski / Alexander I Sobolevsky / |
PubMed 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 ...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. |
External links | Neuron / PubMed:30122377 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.9 - 4.8 Å |
Structure data | EMDB-7959, PDB-6dlz: EMDB-7960, PDB-6dm0: |
Chemicals | ChemComp-GLU: ChemComp-CYZ: ChemComp-GZD: ChemComp-GYY: ChemComp-LU7: |
Source |
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Keywords | TRANSPORT PROTEIN / Ion channel |