Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD

Neuron. 2002 Nov 14;36(4):661-74. doi: 10.1016/s0896-6273(02)01024-3.

Abstract

Proteins that bind to the cytoplasmic tails of AMPA receptors control receptor trafficking and thus the strength of postsynaptic responses. Here we show that AP2, a clathrin adaptor complex important for endocytosis, associates with a region of GluR2 that overlaps the NSF binding site. Peptides used previously to interfere with NSF binding also antagonize GluR2-AP2 interaction. Using GluR2 mutants and peptide variants that dissociate NSF and AP2 interaction, we find that AP2 is involved specifically in NMDA receptor-induced (but not ligand-dependent) internalization of AMPA receptors, and is essential for hippocampal long-term depression (LTD). NSF function, on the other hand, is needed to maintain synaptic AMPA receptor responses, but is not directly required for NMDA receptor-mediated internalization and LTD.

Publication types

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

MeSH terms

  • Adaptor Protein Complex 2 / antagonists & inhibitors
  • Adaptor Protein Complex 2 / metabolism*
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Endocytosis / drug effects
  • Endocytosis / physiology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • N-Ethylmaleimide-Sensitive Proteins
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Peptide Fragments / pharmacology
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / deficiency*
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / genetics
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Vesicular Transport Proteins*

Substances

  • Adaptor Protein Complex 2
  • Carrier Proteins
  • Excitatory Amino Acid Agonists
  • Peptide Fragments
  • Receptors, AMPA
  • Vesicular Transport Proteins
  • N-Ethylmaleimide-Sensitive Proteins
  • Nsf protein, rat
  • glutamate receptor ionotropic, AMPA 2