RT Journal Article
SR Electronic
T1 Subunit-Specific Roles of Glycine-Binding Domains in Activation of NR1/NR3 <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 112
OP 122
DO 10.1124/mol.106.030700
VO 71
IS 1
A1 Marc Awobuluyi
A1 Jin Yang
A1 Yuzhen Ye
A1 Jon E. Chatterton
A1 Adam Godzik
A1 Stuart A. Lipton
A1 Dongxian Zhang
YR 2007
UL http://molpharm.aspetjournals.org/content/71/1/112.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics