Structural and mechanistic determinants of a novel site for non-competitive inhibition of GluN2D-containing NMDA receptors

• Authors: Kasper B. Hansen, Emory University; Stephen Traynelis, Emory University
• Journal Title: Journal of Neuroscience Nursing
• Volume: Volume 31, Number 10
• Publisher: Society for Neuroscience | 2011-03-09, Pages 3650-3661
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.5565-10.2011
• Subjects: Biology, Neuroscience; Health Sciences, Pharmacology
• Keywords: patch-clamp electrophysiology; Xenopus oocytes; pharmacology; allosteric modulation

Abstract

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in several neurological diseases. We have evaluated the mechanism of action of a class of novel subunit-selective NMDA receptor antagonists, typified by (E)-4-(6-methoxy-2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)-benzoic acid (QNZ46). We found that QNZ46 inhibits NMDA receptor function in a non-competitive and voltage-independent manner by an unconventional mechanism that requires binding of glutamate to the GluN2 subunit, but not glycine binding to the GluN1 subunit. This dependency of antagonist association on glutamate binding to GluN2 renders these compounds nominally use-dependent, since inhibition will rely on synaptic release of glutamate. Evaluation of the structural determinants responsible for the subunit-selectivity of QNZ46 revealed that these compounds act at a new site that has not previously been described. Residues residing in the part of the agonist binding domain immediately adjacent to the transmembrane helices appear to control selectivity of QNZ46 for GluN2C- and GluN2D-containing receptors. These residues are well-positioned to sense glutamate binding to GluN2 and thus mediate glutamate-dependent actions. This new class of non-competitive antagonists could provide an opportunity for the development of pharmacological tools and therapeutic agents that target NMDA receptors at a new site and modulate function by a novel mechanism.