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À propos de : Uncompetitive Antagonism of AMPA Receptors: Mechanistic Insights from Studies ofPolyamine Toxin Derivatives        

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  • Uncompetitive Antagonism of AMPA Receptors: Mechanistic Insights from Studies ofPolyamine Toxin Derivatives
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  • Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to thepore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small libraryof novel philanthotoxins was designed and synthesized using a solid-phase strategy. The biological activitieswere investigated at cloned and “native” AMPA receptors using electrophysiological techniques. A distinctrelationship between length of the polyamine moiety and the location of a secondary amino group wasobserved. Fitting the data to the Woodhull equation allowed the first experimental demonstration of therelative location and orientation of the philanthotoxin molecule in the receptor. These results were corroboratedby in silico studies using a homology model of the AMPA receptor ion channel. Together these studiesprovide strong evidence for a molecular mechanism by which polyamine toxins antagonize the AMPAreceptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPAreceptors.
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