title: Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors.
abstract: N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors that mediate a majority of excitatory synaptic transmission. One unique property of GluN1/GluN2D NMDA receptors is an unusually prolonged deactivation time course following the removal of L-glutamate. Here we show, using x-ray crystallography and electrophysiology, that the deactivation time course of GluN1/GluN2D receptors is influenced by the conformational variability of the ligand-binding domain (LBD) as well as the structure of the activating ligand. L-glutamate and L-CCG-IV induce significantly slower deactivation time courses compared with other agonists. Crystal structures of the isolated GluN2D LBD in complex with various ligands reveal that the binding of L-glutamate induces a unique conformation at the backside of the ligand-binding site in proximity to the region at which the transmembrane domain would be located in the intact receptors. These data suggest that the activity of the GluN1/GluN2D NMDA receptor is controlled distinctively by the endogenous neurotransmitter L-glutamate.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road, Atlanta, Georgia 30322-3090, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.forename: Noriko
authors.initials: N
authors.lastname: Simorowski
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: Hiro
authors.initials: H
authors.lastname: Furukawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C464436:NR2D NMDA receptor