Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization

Sainlos, Matthieu, Tigaret, Cezar ORCID: https://orcid.org/0000-0001-5848-6697, Poujol, Christel, Olivier, Nelson B, Bard, Lucie, Breillat, Christelle, Thiolon, Kevin, Choquet, Daniel and Imperiali, Barbara 2011. Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization. Nature Chemical Biology 7 (2) , pp. 81-91. 10.1038/nchembio.498

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Abstract

The interactions of the AMPA receptor (AMPAR) auxiliary subunit Stargazin with PDZ domain–containing scaffold proteins such as PSD-95 are critical for the synaptic stabilization of AMPARs. To investigate these interactions, we have developed biomimetic competing ligands that are assembled from two Stargazin-derived PSD-95/DLG/ZO-1 (PDZ) domain–binding motifs using 'click' chemistry. Characterization of the ligands in vitro and in a cellular FRET-based model revealed an enhanced affinity for the multiple PDZ domains of PSD-95 compared to monovalent peptides. In cultured neurons, the divalent ligands competed with transmembrane AMPAR regulatory protein (TARP) for the intracellular membrane-associated guanylate kinase resulting in increased lateral diffusion and endocytosis of surface AMPARs, while showing strong inhibition of synaptic AMPAR currents. This provides evidence for a model in which the TARP-containing AMPARs are stabilized at the synapse by engaging in multivalent interactions. In light of the prevalence of PDZ domain clusters, these new biomimetic chemical tools could find broad application for acutely perturbing multivalent complexes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	Nature Research (part of Springer Nature)
ISSN:	1552-4450
Date of First Compliant Deposit:	14 January 2020
Date of Acceptance:	8 November 2010
Last Modified:	26 Oct 2022 08:52
URI:	https://orca.cardiff.ac.uk/id/eprint/128525

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