Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel
| Autor: | Edward Y. Shi, Linda M. Nowak, Robert E. Oswald, Jayasri Srinivasan, Christopher P. Ptak, Christine Yuan |
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| Rok vydání: | 2018 |
| Předmět: |
010405 organic chemistry
Chemistry Protein subunit Organic Chemistry Allosteric regulation Antagonist Glutamate receptor Gating AMPA receptor 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Perampanel chemistry.chemical_compound nervous system Postsynaptic potential Drug Discovery Biophysics |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:237-242 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00322 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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