Structure and mechanism of kainate receptor modulation by anions.
L-glutamate, the major excitatory neurotransmitter in the human brain, activates a family of ligand-gated ion channels, the major subtypes of which are named AMPA, kainate, and NMDA receptors. In common with many signal transduction proteins, glutamate receptors are modulated by ions and small molecules, including Ca(2+), Mg(2+), Zn(2+), protons, polyamines, and steroids. Strikingly, the activation of kainate receptors by glutamate requires the presence of both Na(+) and Cl(-) in the extracellular solution, and in the absence of these ions, receptor activity is abolished. Here, we identify the site and mechanism of action of anions. Surprisingly, we find that Cl(-) ions are essential structural components of kainate receptors. Cl(-) ions bind in a cavity formed at the interface between subunits in a dimer pair. In the absence of Cl(-), dimer stability is reduced, the rate of desensitization increases, and the fraction of receptors competent for activation by glutamate drops precipitously.
Plested
Andrew J R
AJ
Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Mayer
Mark L
ML
D000838:Anions / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002461:Cell Line, Transformed; D003461:Crystallography / Q000379:methods; D004347:Drug Interactions; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D008958:Models, Molecular; D016296:Mutagenesis / Q000502:physiology; D018408:Patch-Clamp Techniques; D011487:Protein Conformation / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods
D000838:Anions; D018698:Glutamic Acid; D018092:Kainic Acid Receptors