Received for publication September 11, 2006.
Revised October 13, 2006.
Accepted for publication October 17, 2006.

Subunit-specific Roles of Gycine-Binding Domains in Activation of NR1/NR3 "NMDA" Receptors

Abstract

NMDA receptors (NMDARs) comprised 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, presumably 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 activate NR1/NR3 receptors only poorly, whereas other NR1 agonists are as potent as glycine. Furthermore, liganded NR3 subunits appear 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 amongst ligand-gated ion channel subunits.

Key words: Glutamate, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches

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