Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor

Cell. 2006 Oct 6;127(1):85-97. doi: 10.1016/j.cell.2006.08.037.


The canonical conformational states occupied by most ligand-gated ion channels, and many cell-surface receptors, are the resting, activated, and desensitized states. While the resting and activated states of multiple receptors are well characterized, elaboration of the structural properties of the desensitized state, a state that is by definition inactive, has proven difficult. Here we use electrical, chemical, and crystallographic experiments on the AMPA-sensitive GluR2 receptor, defining the conformational rearrangements of the agonist binding cores that occur upon desensitization of this ligand-gated ion channel. These studies demonstrate that desensitization involves the rupture of an extensive interface between domain 1 of 2-fold related glutamate-binding core subunits, compensating for the ca. 21 degrees of domain closure induced by glutamate binding. The rupture of the domain 1 interface allows the ion channel to close and thereby provides a simple explanation to the long-standing question of how agonist binding is decoupled from ion channel gating upon receptor desensitization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Dimerization
  • Disulfides / chemistry
  • Electrophysiology
  • Glutamic Acid / metabolism
  • Humans
  • Mesylates / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Oocytes / physiology
  • Point Mutation
  • Protein Structure, Quaternary*
  • Rats
  • Receptors, AMPA / chemistry*
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Sulfhydryl Reagents / chemistry
  • Xenopus laevis
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism


  • Disulfides
  • Mesylates
  • Receptors, AMPA
  • Sulfhydryl Reagents
  • (2-sulfonatoethyl)methanethiosulfonate
  • Glutamic Acid
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Cysteine
  • glutamate receptor ionotropic, AMPA 2

Associated data

  • PDB/2I3V
  • PDB/2I3W