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Cell Rep. 2014 Oct 23;9(2):728-40. doi: 10.1016/j.celrep.2014.09.029. Epub 2014 Oct 16.

Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.

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Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address:


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.

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