# 3D Structure and Function of Ligand-Gated Ion Channels

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $336,875

## Abstract

Ionotropic glutamate receptors (iGluRs) are glutamate-activated, cation-selective ion channels that mediate the
majority of millisecond-time scale signaling in the nervous system. The iGluR family of receptors is composed
of three major subtypes, the AMPA, NMDA and kainate receptors, each of which plays a crucial role in nervous
system development and function. The disruption of normal glutamatergic signaling underpins multiple
neurological disorders, including Alzheimer’s disease, depression, schizophrenia and epilepsy. Accordingly,
iGluRs are the targets for numerous therapeutic agents to treat seizure and mood disorders, as well as
schizophrenia. Several immunological disorders of the nervous system also involve iGluRs, with the most
prevalent being NMDA receptor encephalitis, a severe autoimmune disease for which there are few promising
treatments. Despite the widespread distribution of iGluRs throughout the human nervous system, and even
though they are involved in many debilitating neurological diseases and disorders, the molecular mechanisms
of iGluR function are not yet fully elucidated. Moreover, iGluRs are not isolated at their sites of function,
typically the synapses, but rather are found in complexes with multiple auxiliary proteins. Indeed, the
organization and molecular function of these auxiliary proteins also remains to be fully elucidated. Thus, the
major focus of the research proposed in this grant application is to elucidate the molecular structure and
mechanisms of function for AMPA and NMDA receptors, alone and in complexes with key auxiliary proteins.
Here we will develop methods to isolate native AMPA receptors from whole brain and from the hippocampus
and cerebellum, as complexes with their auxiliary proteins. We will then elucidate the structures of these
receptor complexes by single particle cryo-EM, using subunit specific antibody fragments to tag subunits. With
the structures in hand, we will design mutants to test important aspects of structure and mechanisms, carrying
out biochemical and electrophysiological experiments to probe receptor function. In parallel, we will also study
the NMDA receptors, here focusing on a structure-based mechanism for receptor gating, investigating the
structure of the GluN1/GluN2A receptor in complexes with the agonists glycine and glutamate, as well as with
allosteric modulators and ion channel blockers. Through these studies we aim to answer the question of how
neurotransmitters activate the receptor and how allosteric modulators increase or decrease receptor activity.
In parallel with AMPA receptor studies, we will also isolate native GluN1-containing NMDA receptors from
rodent brain tissue, with the aim being to elucidate the first structure of native NMDA receptors, mapping the
positions of the GluN1 and GluN2 subunits in the receptor complex. Taken together, our studies will define
structure-based, biochemical mechanisms for iGluR function and they will lay the foundation for deve...

## Key facts

- **NIH application ID:** 10119334
- **Project number:** 5R01NS038631-24
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** James E Gouaux
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 1999-03-19 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119334

## Citation

> US National Institutes of Health, RePORTER application 10119334, 3D Structure and Function of Ligand-Gated Ion Channels (5R01NS038631-24). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119334. Licensed CC0.

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