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The Journal of Neuroscience, August 8, 2007, 27(32):8505-8516; doi:10.1523/JNEUROSCI.1395-07.2007

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

Joshua B. Silverman,¹ Sophie Restituito,¹ Wei Lu,² Laveria Lee-Edwards,¹ Latika Khatri,¹ and Edward B. Ziff¹

¹Department of Biochemistry and ²Program in Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016

Correspondence should be addressed to Dr. Edward B. Ziff, Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Email: edward.ziff{at}med.nyu.edu

Cadherins function in the adhesion of presynaptic and postsynaptic membranes at excitatory synapses. Here we show that the cadherin-associated 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.

Key words: GluR2; AMPA receptor; ABP; GRIP; cadherin; NPRAP

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Received March 3, 2006; revised June 13, 2007; accepted June 20, 2007.

Correspondence should be addressed to Dr. Edward B. Ziff, Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Email: edward.ziff{at}med.nyu.edu

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