Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling

Cell Rep. 2014 Oct 23;9(2):712-27. doi: 10.1016/j.celrep.2014.09.017. Epub 2014 Oct 9.

Abstract

The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptor Protein Complex 2 / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Endosomes / metabolism*
  • Molecular Sequence Data
  • Neurons / metabolism
  • Protein Binding
  • Protein Transport
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Protein Complex 2
  • Receptors, N-Methyl-D-Aspartate
  • Tumor Suppressor Proteins
  • scribble protein, rat
  • N-methyl D-aspartate receptor subtype 2A