# Mechanism and physiology of NMDA receptor desensitization

> **NIH NIH F30** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $50,520

## Abstract

PROJECT SUMMARY
NMDA receptor hypofunction has been implicated in neuropsychiatric disorders such as schizophrenia, a
disabling mental disorder that affects over 2.2 million patients in the US. One modality for NMDA receptor
hypofunction is aberrant gating, the process where the receptor converts glutamate binding into opening of
the associated ion channel. One pathway to regulate hypofunction is NMDA receptor desensitization, a
gating configuration where the receptor is ligand-bound, but the ion channel is non-conducting. However, its
physiological and mechanistic basis is poorly defined in part because of the lack of tools to study it. In this
proposal I will take advantage of new tools – single site mutations that selectively alter specific features of
NMDA receptor desensitization recently discovered in the Wollmuth lab – as well as cutting edge
technologies to address the mechanism and physiology of NMDA receptor desensitization.
 Whereas desensitization in non-NMDA receptors depends almost exclusively on the rearrangement
of the ligand-binding domain (LBD) dimer interface, such a mechanism is less significant in NMDA receptors
and all domains, most notably the transmembrane domain (TMD), have been implicated in NMDA receptor
desensitization. In Aim 1, I will test the general hypothesis that the mechanism of NMDA receptor
desensitization is fundamentally different from that of non-NMDA receptors, depending strongly on the
conformation of the ion channel. To test this hypothesis, I will take advantage of newly identified single-site
mutations, patch clamp electrophysiology as well as techniques to regulate the subunit composition of
NMDA receptors and light-activated unnatural amino acids. These experiments will help define the structural
mechanisms that govern NMDA receptor desensitization, aiding in the development of novel therapeutics
that can selectively modulate NMDA receptor activity by specifically targeting desensitization.
In Aim 2, I will test the hypothesis that NMDA receptor desensitization leads to decreased excitatory signaling
at synapses during high activity. Indeed, my preliminary data show that fast applications of glutamate caused
a higher degree of current decay in these mutants, suggesting a potential role of desensitization in NMDA
hypofunction. To test this hypothesis more rigorously, I will express mutant NMDA receptors that have
altered desensitization properties in organotypic hippocampal slice cultures to address how they change
synaptic dynamics including Ca2+ influx and synaptic plasticity. These experiments will address how NMDA
receptor desensitization contributes to synaptic physiology.
 The information gained by the experiments in this proposal will provide insight into the mechanism
of NMDA receptor desensitization and its role in synaptic dynamics. My experiments will aid in the
development of novel therapeutics that selectively modulates NMDA receptor activity by specifically
targeting desensitization.

## Key facts

- **NIH application ID:** 10001637
- **Project number:** 5F30MH115618-04
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Kelvin Chan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-09-27 → 2021-09-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001637

## Citation

> US National Institutes of Health, RePORTER application 10001637, Mechanism and physiology of NMDA receptor desensitization (5F30MH115618-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001637. Licensed CC0.

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