Structural determinants of allosteric regulation in alternatively spliced AMPA receptors

Neuron. 1995 Apr;14(4):833-43. doi: 10.1016/0896-6273(95)90227-9.


The flip and flop splice variants of AMPA receptors show strikingly different sensitivity to allosteric regulation by cyclothiazide; heteromers assembled from GluR-A and GluR-B also exhibit splice variant-dependent differences in efficacy for activation by glutamate and kainate. The sensitivity for attenuation of desensitization by cyclothiazide for homomeric GluR-A was solely dependent upon exchange of Ser-750 (flip) and Asn-750 (flop), and was unaffected by mutagenesis of other divergent residues. In contrast, substantial alteration of the relative efficacy of glutamate versus kainate required mutation of multiple residues in the flip/flop region. Modulation by cyclothiazide was abolished by mutation of Ser-750 to Gin, the residue found at the homologous site in kainate-preferring subunits, whereas introduction of Ser at this site in GluR6 imparted sensitivity to cyclothiazide.

MeSH terms

  • Allosteric Regulation / drug effects
  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Benzothiadiazines / pharmacology
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Glutamic Acid / pharmacology
  • Glutamine
  • Humans
  • Kainic Acid / pharmacology
  • Kidney
  • Macromolecular Substances
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oocytes / metabolism
  • Point Mutation
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / genetics*
  • Receptors, Kainic Acid / chemistry
  • Serine
  • Transfection
  • Xenopus laevis


  • Benzothiadiazines
  • Macromolecular Substances
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Glutamine
  • Glutamic Acid
  • Serine
  • cyclothiazide
  • Kainic Acid