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Mapping the Interaction Sites between AMPA Receptors and TARPs Reveals a Role for the Receptor N-Terminal Domain in Channel Gating

Cais, O; Herguedas, B; Krol, K; Cull-Candy, SG; Farrant, M; Greger, IH; (2014) Mapping the Interaction Sites between AMPA Receptors and TARPs Reveals a Role for the Receptor N-Terminal Domain in Channel Gating. Cell Reports , 9 (2) pp. 728-740. 10.1016/j.celrep.2014.09.029. Green open access

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Abstract

AMPA-type glutamate receptors (AMPARs) mediate fast neurotransmission at excitatory synapses. The extent and fidelity of postsynaptic depolarization triggered by AMPAR activation are shaped by AMPAR auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). TARPs profoundly influence gating, an effect thought to be mediated by an interaction with the AMPAR ion channel and ligand binding domain (LBD). Here, we show that the distal N-terminal domain (NTD) contributes to TARP modulation. Alterations in the NTD-LBD linker result in TARP-dependent and TARP-selective changes in AMPAR gating. Using peptide arrays, we identify a TARP interaction region on the NTD and define the path of TARP contacts along the LBD surface. Moreover, we map key binding sites on the TARP itself and show that mutation of these residues mediates gating modulation. Our data reveal a TARP-dependent allosteric role for the AMPAR NTD and suggest that TARP binding triggers a drastic reorganization of the AMPAR complex.

Type: Article
Title: Mapping the Interaction Sites between AMPA Receptors and TARPs Reveals a Role for the Receptor N-Terminal Domain in Channel Gating
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2014.09.029
Publisher version: http://doi.org/10.1016/j.celrep.2014.09.029
Language: English
Additional information: Copyright © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, IONOTROPIC GLUTAMATE RECEPTORS, LIGAND-BINDING DOMAIN, CRYSTAL-STRUCTURE, AUXILIARY SUBUNITS, SYNAPTIC CURRENTS, MOLECULAR-BASIS, NMDA RECEPTORS, TIME-COURSE, DESENSITIZATION, TRAFFICKING
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1454096
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