Paul Ornstein - Transmembrane AMPA Receptor Regulatory Proteins and Cornichon-2 Allosterically Regulate AMPA Receptor Antagonists and Potentiators

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      Schober, Douglas A., Gill, Martin B., Yu, Hong, Gernert, Douglas   L., Jeffries, Matthew W., Ornstein, Paul L., Kato, Akihiko S.,   Felder, Christian C., Bredt, David S. Journal of Biological   Chemistry 2011 286 (15)   13134-13142

      Abstract: AMPA receptors mediate fast excitatory   transmission in the brain. Neuronal AMPA receptors comprise GluA   pore-forming principal subunits and can associate with multiple   modulatory components, including transmembrane AMPA receptor   regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor   potentiators and non-competitive antagonists represent potential   targets for a variety of neuropsychiatric disorders. Previous   studies showed that the AMPA receptor antagonist GYKI-53655   displaces binding of a potentiator from brain receptors but not   from recombinant Cilia subunits. Here, we asked whether AMPA   receptor modulatory subunits might resolve this discrepancy. We   find that the cerebellar TARP, stargazin (gamma-2), enhances the   binding affinity of the AMPA receptor potentiator [H-3]-LY450295   and confers sensitivity to displacement by non-competitive   antagonists. In cerebellar membranes from stargazer mice,   [H-3]-LY450295 binding is reduced and relatively resistant to   displacement by non-competitive antagonists. Coexpression of AMPA   receptors with CNIH-2, which is expressed in the hippocampus and   at low levels in the cerebellar Purkinje neurons, confers partial   sensitivity of [H-3] -LY450295 potentiator binding to   displacement by non-competitive antagonists. Autoradiography of   [H-3]-LY450295 binding to stargazer and gamma-8-deficient mouse   brain sections, demonstrates that TARPs regulate the pharmacology   of allosteric AMPA potentiators and antagonists in the cerebellum   and hippocampus, respectively. These studies demonstrate that   accessory proteins define AMPA receptor pharmacology by   functionally linking allosteric AMPA receptor potentiator and   antagonist sites.

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