# Regulation of excitotoxicity by ZnT1

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $412,150

## Abstract

This year marks the 50th anniversary of John Olney’s seminal work that introduced the concept of excitotoxicity
as a mechanism for neuronal cell death. Since that time, fundamental research on the pathophysiological
activation of NMDA receptors has played a central role in our understanding of excitotoxic cellular signaling
pathways, leading to the discovery of many potential therapeutic targets in the treatment of acute or
chronic/progressive neurodegenerative disorders. Despites countless efforts, however, translational strategies
aimed at inhibiting or regulating NMDA receptor-mediated excitotoxic injury have repeatedly failed in clinical
trials, leaving only very few potential applications viable today. Nonetheless, highly innovative approaches in
this important area of research could still yield tangible advances in the field of neuroprotection. We this in mind,
we introduce here a previously unrecognized modulator of NMDA receptor-mediated excitotoxicity, namely, the
ZnT1 (Slc30a1) zinc transporter. We present preliminary data showing that the interaction between ZnT1 and
the highly zinc sensitive NMDA receptor subunit GluN2A strongly dictate the inhibitory, regulatory function of the
metal on the receptor. Moreover, we reveal the development of a cell-penetrating peptide designed to specifically
reduce the interaction between ZnT1 and GluN2A influences NMDA receptor-mediated synaptic responses. We
tailor the proposed work by taking advantage of an endogenous neuronal mechanism of zinc-dependent
excitotoxic tolerance, and utilize both in vitro and in vivo experimental approaches to achieve the proposed aims,
which are: i) to investigate the role of the GluN2A-ZnT1 interaction in regulating NMDA excitotoxicity in vitro,
and ii) to establish the role of ZnT1 upregulation and increased GluN2A-ZnT1 interaction in an in vivo model of
ischemic preconditioning. If successful, the work proposed in this Exploratory/Development Research Grant
(R21) proposal will define an novel approach to regulate NMDA receptor-mediated excitotoxic injury, with
translational potential in future work.

## Key facts

- **NIH application ID:** 10032716
- **Project number:** 1R21NS117702-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Elias Aizenman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,150
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10032716

## Citation

> US National Institutes of Health, RePORTER application 10032716, Regulation of excitotoxicity by ZnT1 (1R21NS117702-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10032716. Licensed CC0.

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