Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins.
The relative content of NR2 subunits in the NMDA receptor confers specific signaling properties and plasticity to synapses. However, the mechanisms that dynamically govern the retention of synaptic NMDARs, in particular 2A-NMDARs, remain poorly understood. Here, we investigate the dynamic interaction between NR2 C termini and proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) scaffold proteins at the single molecule level by using high-resolution imaging. We report that a biomimetic divalent competing ligand, mimicking the last 15 amino acids of NR2A C terminus, specifically and efficiently disrupts the interaction between 2A-NMDARs, but not 2B-NMDARs, and PDZ proteins on the time scale of minutes. Furthermore, displacing 2A-NMDARs out of synapses lead to a compensatory increase in synaptic NR2B-NMDARs, providing functional evidence that the anchoring mechanism of 2A- or 2B-NMDARs is different. These data reveal an unexpected role of the NR2 subunit divalent arrangement in providing specific anchoring within synapses, highlighting the need to study such dynamic interactions in native conditions.
Laboratory for Cellular Physiology of the Synapse, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5091, 33077 Bordeaux, France.
Lucie
L
Bard
Matthieu
M
Sainlos
Delphine
D
Bouchet
Sarah
S
Cousins
Lenka
L
Mikasova
Christelle
C
Breillat
F Anne
FA
Stephenson
Barbara
B
Imperiali
Daniel
D
Choquet
Laurent
L
Groc
D000818:Animals; D007700:Kinetics; D009473:Neuronal Plasticity; D009842:Oligopeptides / Q000494:pharmacology; D054731:PDZ Domains; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000737:chemistry*; D009435:Synaptic Transmission
D009842:Oligopeptides; D010446:Peptide Fragments; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate