Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization.
Nat Chem Biol. 2010-12-26; 7(2): 81-91
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1. Nat Chem Biol. 2011 Feb;7(2):81-91. doi: 10.1038/nchembio.498. Epub 2010 Dec 26.
Biomimetic divalent ligands for the acute disruption of synaptic AMPAR
Sainlos M(1), Tigaret C, Poujol C, Olivier NB, Bard L, Breillat C, Thiolon K,
Choquet D, Imperiali B.
(1)Department of Chemistry and Department of Biology, Massachusetts Institute of
Technology, Cambridge, Massachusetts, USA.
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.
PMID: 21186349 [Indexed for MEDLINE]