Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting

Neuron. 2000 Nov;28(2):511-25. doi: 10.1016/s0896-6273(00)00129-x.


Both acute and chronic changes in AMPA receptor (AMPAR) localization are critical for synaptic formation, maturation, and plasticity. Here I report that AMPARs are differentially sorted between recycling and degradative pathways following endocytosis. AMPAR sorting occurs in early endosomes and is regulated by synaptic activity and activation of AMPA and NMDA receptors. AMPAR intemalization triggered by NMDAR activation is Ca2+-dependent, requires protein phosphatases, and is followed by rapid membrane reinsertion. Furthermore, NMDAR-mediated AMPAR trafficking is regulated by PKA and accompanied by dephosphorylation and rephosphorylation of GluR1 subunits at a PKA site. In contrast, activation of AMPARs without NMDAR activation targets AMPARs to late endosomes and lysosomes, independent of Ca2+, protein phosphatases, or PKA. These results demonstrate that activity regulates AMPAR endocytic sorting, providing a potential mechanistic link between rapid and chronic changes in synaptic strength.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Compartmentation / physiology
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Endosomes / metabolism
  • GABA Antagonists / pharmacology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Picrotoxin / pharmacology
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Rats
  • Receptors, AMPA / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tetrodotoxin / pharmacology


  • GABA Antagonists
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Picrotoxin
  • Tetrodotoxin
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • Calcium