Activity-regulated N-cadherin endocytosis

Neuron. 2007 Jun 7;54(5):771-85. doi: 10.1016/j.neuron.2007.05.013.

Abstract

Enduring forms of synaptic plasticity are thought to require ongoing regulation of adhesion molecules, such as N-cadherin, at synaptic junctions. Little is known about the activity-regulated trafficking of adhesion molecules. Here we demonstrate that surface N-cadherin undergoes a surprisingly high basal rate of internalization. Upon activation of NMDA receptors (NMDAR), the rate of N-cadherin endocytosis is significantly reduced, resulting in an accumulation of N-cadherin in the plasma membrane. Beta-catenin, an N-cadherin binding partner, is a primary regulator of N-cadherin endocytosis. Following NMDAR stimulation, beta-catenin accumulates in spines and exhibits increased binding to N-cadherin. Overexpression of a mutant form of beta-catenin, Y654F, prevents the NMDAR-dependent regulation of N-cadherin internalization, resulting in stabilization of surface N-cadherin molecules. Furthermore, the stabilization of surface N-cadherin blocks NMDAR-dependent synaptic plasticity. These results indicate that NMDAR activity regulates N-cadherin endocytosis, providing a mechanistic link between structural plasticity and persistent changes in synaptic efficacy.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • COS Cells
  • Cadherins / metabolism*
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Dendritic Spines / metabolism*
  • Dendritic Spines / ultrastructure
  • Endocytosis / physiology*
  • Hippocampus / cytology
  • Hippocampus / growth & development*
  • Hippocampus / metabolism*
  • Humans
  • Mice
  • Microscopy, Confocal
  • Mutation / genetics
  • Neuronal Plasticity / physiology
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Protein Binding / physiology
  • Protein Transport / physiology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Cadherins
  • Receptors, N-Methyl-D-Aspartate
  • beta Catenin