title: Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-D-aspartate receptors.
abstract: N-Methyl-D-aspartate receptors (NMDARs) composed of NR1 and NR3 subunits differ from other NMDAR subtypes in that they require glycine alone for activation. However, little else is known about the activation mechanism of these receptors. Using NMDAR glycine-site agonists/antagonists in conjunction with functional mutagenesis of the NR1 and NR3 ligand-binding cores, we demonstrate quite surprisingly that agonist binding to NR3 alone is sufficient to activate a significant component of NR1/NR3 receptor currents. Thus, the apo conformation of NR1 in NR1/NR3 receptors is permissive for receptor activation. Agonist-bound NR1 may also contribute to peak NR1/NR3 receptor currents but specifically enables significant NR1/NR3 receptor current decay under the conditions studied here, pre-sumably via a slow component of desensitization. Ligand studies of NR1/NR3 receptors also suggest differential agonist selectivity between NR3 and NR1, as some high-affinity NR1 agonists only minimally activate NR1/NR3 receptors, whereas other NR1 agonists are as potent as glycine. Furthermore, liganded NR3 subunits seem necessary for effective engagement of NR1 in NR1/NR3 receptor activation, suggesting significant interactivity between the two subunits. NR3 subunits thus induce plasticity in NR1 with respect to subunit assembly and ligand binding/channel coupling that is unique among ligand-gated ion channel subunits.
authors.affiliation: Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Awobuluyi
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Ye
authors.forename: Jon E
authors.initials: JE
authors.lastname: Chatterton
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins; D018909:src Homology Domains
chemical_list: C409466:NR1 NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D005998:Glycine