Functional stoichiometry of glutamate receptor desensitization.
Potassium (K+) channels and ionotropic glutamate receptors (iGluRs) fulfill divergent roles in vertebrate nervous systems. Despite this, however, recent work suggests that these ion channels are structurally homologous, sharing an ancestral protein, architectural design, and tetrameric subunit stoichiometry. Their gating mechanisms also are speculated to have overlapping features. Here we show that the mechanism of iGluR desensitization is unique. Unlike K+ channels, AMPA- and kainate-type iGluR subunits desensitize in several ordered conformational steps. AMPA receptors operate as dimers, whereas the functional stoichiometry of kainate receptor desensitization is dependent on external ions. Contrary to conventional understanding, kinetic models suggest that partially desensitized AMPA and kainate receptors conduct ions and are likely participants in synaptic signaling. Although sharing many structural correlates with K+ channels, iGluRs have evolved unique subunit-subunit interactions, tailoring their gating behavior to fulfill distinct roles in neuronal signaling.
Bowie
Derek
D
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. dbowie@pharm.emory.edu
Lange
G David
GD
D002460:Cell Line; D019281:Dimerization; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D011930:Reaction Time / Q000502:physiology; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D012965:Sodium Chloride / Q000494:pharmacology; D014162:Transfection; D000097806:GluK2 Kainate Receptor
D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D012965:Sodium Chloride; D000097806:GluK2 Kainate Receptor