The N-terminal domain modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization

J Biol Chem. 2014 May 9;289(19):13197-205. doi: 10.1074/jbc.M113.526301. Epub 2014 Mar 20.


AMPA receptors are tetrameric glutamate-gated ion channels that mediate fast synaptic neurotransmission in mammalian brain. Their subunits contain a two-lobed N-terminal domain (NTD) that comprises over 40% of the mature polypeptide. The NTD is not obligatory for the assembly of tetrameric receptors, and its functional role is still unclear. By analyzing full-length and NTD-deleted GluA1-4 AMPA receptors expressed in HEK 293 cells, we found that the removal of the NTD leads to a significant reduction in receptor transport to the plasma membrane, a higher steady state-to-peak current ratio of glutamate responses, and strongly increased sensitivity to glutamate toxicity in cell culture. Further analyses showed that NTD-deleted receptors display both a slower onset of desensitization and a faster recovery from desensitization of agonist responses. Our results indicate that the NTD promotes the biosynthetic maturation of AMPA receptors and, for membrane-expressed channels, enhances the stability of the desensitized state. Moreover, these findings suggest that interactions of the NTD with extracellular/synaptic ligands may be able to fine-tune AMPA receptor-mediated responses, in analogy with the allosteric regulatory role demonstrated for the NTD of NMDA receptors.

Keywords: Allosteric Regulation; Ion Channels; Ionotropic Glutamate Receptors (AMPA, NMDA); Protein Domains; Receptor Desensitization; Receptor Structure-Function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Excitatory Amino Acid Agonists / pharmacology*
  • HEK293 Cells
  • Humans
  • Protein Structure, Tertiary
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*


  • Excitatory Amino Acid Agonists
  • Receptors, AMPA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid