RT Journal Article
SR Electronic
T1 Control of AMPA receptor activity by the extracellular loops of auxiliary proteins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 140053
DO 10.1101/140053
A1 Irene Riva
A1 Clarissa Eibl
A1 Rudolf Volkmer
A1 Anna L. Carbone
A1 Andrew J. R. Plested
YR 2017
UL http://biorxiv.org/content/early/2017/05/19/140053.abstract
AB 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 γ2 and γ8, 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 γ2 and γ8, 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 TARPs on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.