# Structural characterization and targeting of tri-heteromeric NMDA receptors involved in neuroplasticity

> **NIH NIH F32** · COLD SPRING HARBOR LABORATORY · 2020 · $64,926

## Abstract

Abstract
The goal of this proposal is to secure three years of postdoctoral research training support in order to
structurally define in detail both GluN1-2A-2B and GluN1-2B-3A N-methyl-D-aspartate receptors (NMDARs)
and to identify modulators that will specifically target these tri-heteromeric receptors without targeting di-
heteromeric receptors. Reagents which specifically recognize and modulate the activity of GluN1-2A-2B and
GluN1-2B-3A have the potential to boost cognition, and may lead to promising therapeutics to treat mental
health disorders including depression, memory loss, and addiction. I have experience in electrophysiology with
a background in ion channels and membrane protein biochemistry, and the proposed research and career
development activities that I plan to pursue during this fellowship will provide the advanced training necessary
to achieve my long-term career objective to be an independent researcher in the field of neuropharmacology.
NMDARs belong to a large family of ionotropic glutamate receptors which are the prevailing regulators of
neural communication, and their misregulation has been linked to numerous mental health disorders. Within
the glutamate receptor family, heterotetrameric NMDARs are integral mediators of electrical and chemical
signaling by sensing neurotransmitter release and transmembrane voltage potential at sites of
neurotransmission known as synapses. Repeated activation of NMDARs results in synaptic plasticity in the
forms of long term potentiation (LTP) and long term depression (LTD), which directly influence brain
development and function including learning and memory. Changes in LTP and LTD are correlated with the
specific activation of two NMDAR subtypes, the tri-heteromeric GluN1-2A-2B and GluN1-2B-3A receptors.
However, how the activation of GluN1-2A-2B or GluN1-2B-3A correlates with changes in synaptic plasticity has
been difficult to discern due to limited structural characterization of tri-heteromeric NMDARs and due to
overlapping pharmacology profiles of these receptors with di-heteromeric NMDARs. In Aim 1, I will determine
the structures of the human orthologues of GluN1-2A-2B and GluN1-2B-3A by cryo-electron microscopy, and
in Aim 2 I will identify and test nanobody modulators that specifically target tri-heteromeric NMDARs using
yeast display. The Furukawa Lab at Cold Spring Harbor Laboratory (CSHL) has vast experience working with
NMDARs and is uniquely positioned to support my proposed aims using optimized NMDAR expression
strategies, electrophysiology setups, and structural biology expertise. Additionally, I will have immediate
access to a state-of-the-art cryo-EM facility as well as an on-campus Antibody and Display facility, which are
both managed by highly regarded technical staff. The research proposed here will allow me to gain
tremendous experience in modern structural biology techniques, display strategies used to develop novel
immunotherapies, and has the potential to uncover ...

## Key facts

- **NIH application ID:** 9992078
- **Project number:** 1F32MH121061-01A1
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Kevin Michalski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992078

## Citation

> US National Institutes of Health, RePORTER application 9992078, Structural characterization and targeting of tri-heteromeric NMDA receptors involved in neuroplasticity (1F32MH121061-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9992078. Licensed CC0.

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