Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel

Postsynaptic AMPA/glutamate receptors, essential for neuronal excitability, are important targets for anticonvulsant therapy. This single channel study of the selective noncompetitive AMPA receptor antagonist, perampanel, was performed on homotetrameric GluA3 receptor-channels that open in a stepwis...

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Published in:ACS medicinal chemistry letters 2019-03, Vol.10 (3), p.237-242
Main Authors: Yuan, Christine L, Shi, Edward Y, Srinivasan, Jayasri, Ptak, Christopher P, Oswald, Robert E, Nowak, Linda M
Format: Article
Language:English
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Letter
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Summary:Postsynaptic AMPA/glutamate receptors, essential for neuronal excitability, are important targets for anticonvulsant therapy. This single channel study of the selective noncompetitive AMPA receptor antagonist, perampanel, was performed on homotetrameric GluA3 receptor-channels that open in a stepwise manner to four distinct conductance levels through independent subunit activation. Previous structural studies show that perampanel binds to four sites located within the extracellular/transmembrane boundary of closed AMPA receptor-channel subunits. We found that channels exposed to 1 or 2 μM perampanel opened mainly to the two lower conductance levels in a dose-dependent manner. Comparison of the single channel results in the structures of the full length AMPA receptor in the closed state bound to perampanel, and the open state provide insights into the mechanism of allosteric reduction of AMPA-receptor-mediated excitation in epilepsy.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00322