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bioRxiv · 10.1101/140053

Control Of AMPA Receptor Activity By The Extracellular Loops Of Auxiliary Proteins

Riva, I.·Eibl, C.·Volkmer, R.·Carbone, A. L.·Plested, A.
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Abstract

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs {gamma}2 and {gamma}8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of {gamma}2 and {gamma}8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of Y2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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Riva, I., Eibl, C., Volkmer, R., Carbone, A. L., Plested, A.. 2017-05-19. Control Of AMPA Receptor Activity By The Extracellular Loops Of Auxiliary Proteins. https://doi.org/10.1101/140053

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