# Structural and functional investigation of allosteric NMDA receptor modulation

> **NIH NIH R01** · UNIVERSITY OF MONTANA · 2024 · $353,080

## Abstract

NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous
system (CNS) and play critical roles in brain functions. Aberrant NMDA receptor signaling is implicated in many
CNS diseases, and NMDA receptors are receiving widespread interest as therapeutic targets. Although it has
proven difficult to translate preclinical findings into clinical efficacy, the many NMDA receptor ligands from
these studies have created a valuable pharmacological toolbox that continues to support neuroscience
research. Most NMDA receptors are composed of two glycine-binding GluN1 and two glutamate-binding GluN2
subunits. There are four different GluN2 subunits (GluN2A-D) that endow NMDA receptors with distinct
functional properties and different developmental and regional expression in the CNS. Selective modulation of
NMDA receptors that contain a specific GluN2 subunit can therefore target a subset of receptor subtypes
expressed in disease-relevant neuronal populations. NMDA receptors require simultaneous binding of glycine
(or D-serine) to GluN1 and glutamate to GluN2 for activation, but mainly rely on synaptic release of glutamate
for activation in the CNS, since extracellular glycine (or D-serine) is continuously present. Thus, glutamate
binding to GluN2 primarily mediates phasic activation of synaptic NMDA receptors, while agonist occupancy at
GluN1 can modulate response amplitude. We will investigate two distinct modes of NMDA receptor
modulation, both of which display GluN2 subunit-selectivity and affect the GluN1 agonist binding site to
modulate NMDA receptor responses. In Aim 1, we will define binding contacts and mechanism of action for a
new class of GluN2A-selective negative allosteric modulators that bind the subunit interface between GluN1
and GluN2A agonist binding domains (ABDs) to negatively modulate agonist binding to GluN1. In Aim 2, we
will determine the structural basis for GluN2 subunit-specific activity of novel glycine site agonists with
remarkably high potency and unprecedented variation in agonist efficacy among NMDA receptor subtypes. By
replacing endogenous glycine or D-serine, these GluN2-dependent agonists can modulate NMDA receptors
when activated by synaptic glutamate release. In Aim 3, we will modulate neuronal NMDA receptors in acute
rodent brain slices using novel GluN2A-selective NAMs and GluN1 agonists. NMDA receptor-positive neurons
in the adult CNS express at least two different GluN2 subunits and many NMDA receptors are assembled with
two different GluN2 subunits (i.e. triheteromeric receptors). We will evaluate the activity of the novel
modulators at recombinant triheteromeric NMDA receptor subtypes (GluN1/2A/2B, GluN1/2B/2D, and
GluN1/2A/2C) and at native NMDA receptors in distinct neuronal populations with defined expression of these
GluN2 subunit combinations. These investigations will uncover previously unrecognized features of NMDA
receptor modulation and provide new avenues for basic...

## Key facts

- **NIH application ID:** 10740861
- **Project number:** 5R01NS097536-08
- **Recipient organization:** UNIVERSITY OF MONTANA
- **Principal Investigator:** Kasper Boe Hansen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $353,080
- **Award type:** 5
- **Project period:** 2016-08-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740861

## Citation

> US National Institutes of Health, RePORTER application 10740861, Structural and functional investigation of allosteric NMDA receptor modulation (5R01NS097536-08). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10740861. Licensed CC0.

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