Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes

Abstract

Cadherins function in the adhesion of presynaptic and postsynaptic membranes at excitatory synapses. Here we show that the cadherinassociated protein neural plakophilin-related arm protein (NPRAP; also called ␦-catenin) binds via a postsynaptic density-95 (PSD-95)/ discs large/zona occludens-1 (PDZ) interaction to AMPA receptor (AMPAR)-binding protein (ABP) and the related glutamate receptor (GluR)-interacting protein (GRIP), two multi-PDZ proteins that bind the GluR2 and GluR3 AMPAR subunits. The resulting cadherin-NPRAP-ABP/GRIP complexes serve as anchorages for AMPARs. Exogenous NPRAP that was bound to cadherins at adherens junctions of Madin-Darby canine kidney cells recruited ABP from the cytosol to form cadherin-NPRAP-ABP complexes, dependent on NPRAP interaction with the ABP PDZ domain 2. The cadherin-NPRAP-ABP complexes also bound GluR2. In cultured hippocampal neurons, dominant-negative mutants of NPRAP designed to disrupt tethering of ABP to NPRAP-cadherin complexes reduced surface levels of endogenous GluR2, indicating that interaction with cadherin-NPRAP-ABP complexes stabilized GluR2 at the neuronal plasma membrane. Cadherins, NPRAP, GRIP, and GluR2 copurified in the fractionation of synaptosomes and the postsynaptic density, two fractions enriched in synaptic proteins. Furthermore, synaptosomes contain NPRAP-GRIP complexes, and NPRAP localizes with the postsynaptic marker PSD-95 and with AMPARs and GRIP at spines of hippocampal neurons. Thus, tethering is likely to take place at synaptic or perisynaptic sites. NPRAP also binds PSD-95, which is a scaffold for NMDA receptors, for AMPARs in complexes with auxiliary subunits, the TARPs (transmembrane AMPA receptor regulator proteins), and for adhesion molecules. Thus, the interaction of scaffolding proteins with cadherin-NPRAP complexes may anchor diverse signaling and adhesion molecules at cadherins.

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

“…Our observation that other Aβ-driven effects are not observed in GluA3-deficient mice is consistent with the notion that the removal of AMPARs from synapses is one of the first critical steps in Aβ pathogenesis (15, 16), followed or accompanied by the collateral removal of GluA1/2s and GluN2B-containing NMDARs and the disintegration of the synapse. Possibly GluA2/3s play a role in the stabilization of spine structures, for instance through their interaction with N-cadherins at synapses (42,43). Alternatively, the endocytosis of GluA3-containing AMPARs may trigger a cellular signal that leads to the dismantling of spine structures.…”

GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites

“…In this respect, AMPAR/N-cadherin vesicles could harbor additional cargoes such as the scaffolding molecule δ-catenin that anchors GluA2 and N-cadherin at synaptic sites (32). In addition, the extracellular interaction of GluA2 and N-cadherin (7), if it takes place inside the vesicle lumen, could strengthen the stability of the complex.…”

Xenopus δ-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases

“…-catenin associates with multiple proteins of the neural adherens or synaptic junction (Arikkath et al, 2008;Deguchi et al, 2000;Fujita et al, 2004;Ide et al, 1999;Izawa et al, 2002;Jones et al, 2002;Kim et al, 2006;Laura et al, 2002;Lu et al, 2002;Mackie and Aitken, 2005;Martinez et al, 2003;Munoz et al, 2007;Silverman et al, 2007). Most of these interactions occur through its central armadillo domain or its C-terminal PDZ (PSD-95/Discslarge/ZO-1) binding motif.…”