# NRAP-1 control of NMDA receptor-mediated synaptic transmission

> **NIH NIH F32** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $65,310

## Abstract

The NMDA-receptor (NMDAR) subtype of ionotropic glutamate receptors (iGluRs) has
fundamental roles in the processing and encoding of information, and in humans, defects in NMDAR
signaling are a hallmark of many neurological disorders. A recent surprising and unexpected discovery
using a C. elegans genetic screen for modifiers of NMDAR function has revealed that in this organism
the NMDAR does not function autonomously as previously thought, and is instead part of a larger
signaling complex, requiring for its activation the binding of a presynaptically secreted protein, NRAP-1.
In C. elegans, NRAP-1 is rate limiting for NMDAR function, and thus likely controls the magnitude of
NMDAR signaling. Therefore, the mechanisms regulating NRAP-1 secretion, such as the changes in
neuronal activity that regulate synapse plasticity, are likely to have fundamental roles in synaptic
transmission and NMDAR-mediated changes in synapse strength. Aim 1 of this proposal will determine
how neuronal activity regulates the secretion of NRAP-1. To accomplish this, genetic modification and
elimination strategies combined with chemical and light controlled ion channels to selectively silence or
activate neuronal populations will be employed. In vivo live imaging will be used to directly assess
NRAP-1 secretion in response to chronic and acute changes in neuronal activity. The results of this aim
will provide new mechanistic insights into acute and homeostatic control of NMDAR-mediated
signaling and synaptic plasticity. Although NRAP-1 is of critical importance in the gating of NMDARs,
we currently lack a mechanistic understanding of this essential process. Aim 2 of this proposal will
define NRAP-1's mechanism of action in gating NMDAR-mediated currents. To accomplish this I will
use application of purified recombinant NRAP-1 and NRAP-1 mutants to electrophysiological NMDAR
preparations. These constructs will be additionally used in in vitro protein-protein binding assays to
define the functional domains of NRAP-1 as well as how and where it binds to the NMDAR. The results
of this aim will provide insight into the structure and function of the newly identified C. elegans
NMDAR signaling complex. Because of the deep evolutionary conservation of iGluRs and glutamatergic
signaling, we anticipate that similar signaling mechanisms might also contribute to the regulation of
vertebrate NMDAR signaling. Additionally, comparisons of the evolutionary divergence of NMDAR
gating made possible by the results of this study will provide fundamental insights into the design and
function of NMDARs. Thus, our studies will provide new conceptual framework for drug discovery that
could ultimately motivate new approaches for therapeutic intervention in neurological disease
characterized by disrupted NMDAR function.

## Key facts

- **NIH application ID:** 9977001
- **Project number:** 5F32NS110173-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Dayton Joshua Goodell
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977001

## Citation

> US National Institutes of Health, RePORTER application 9977001, NRAP-1 control of NMDA receptor-mediated synaptic transmission (5F32NS110173-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977001. Licensed CC0.

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