# Neuronal Activity-Regulated Glutamine Transporter

> **NIH NIH R21** · LSU HEALTH SCIENCES CENTER · 2020 · $184,511

## Abstract

Abstract. Excitotoxicity is the pathological process by which nerve cells are damaged
and killed by excessive stimulation by the neurotransmitter glutamate. Such excitotoxic
neuronal death has been implicated in cerebral global ischemia and is a result of
excessive presynaptic glutamate release. It is believed that glutamate transmission
requires import of glutamine into axon terminals from astrocytes to replenish cytoplasmic
glutamate levels and vesicular stores lost following excessive synaptic glutamate
release. Thus, blocking synaptic import of glutamine represents a potential therapeutic
target to limit continued glutamate release under conditions of excitotoxicity. We have
recently functionally identified a novel activity-regulated glutamine transporter, which is
potently inhibited by the anti-glutamatergic drug riluzole. Critical barriers to progress in
understanding presynaptic mechanisms involved in excessive glutamate release are 1)
the molecular identity of the neuronal activity-regulated glutamine transporter expressed
in synapses is not known, 2) riluzole derivatives that selectively block the neuronal
activity-regulated glutamine transporter, and that have improved brain penetration, are
not available, and 3) the role of the neuronal activity-regulated glutamine transporter in
vivo has not been determined. Riluzole blocks excessive synaptic glutamate release and
can block neuronal damage that occurs in conditions of excitotoxicity, including global
cerebral ischemia in rodents. We have identified novel riluzole derivatives with superior
brain penetration that potently block neuronal activity-regulated glutamine transport, but
those likely do not interfere with Na+ (i.e., NaV) or K+ (i.e., KV) channels, compared to
riluzole. The functional identification of riluzole-sensitive, neuronal activity-regulated
glutamine transport in hippocampal synapses has important ramifications in the
neurobiology of synaptic glutamate release, the glutamate/glutamine cycle, and
glutamate-induced excitotoxicity. Our overall goal is to improve therapeutic options in
conditions of excessive glutamate release from synapses by providing rationale for
developing drugs to limit activity-driven glutamine import in axon terminals and
replenishment of cytoplasmic glutamate levels required to sustain excitotoxic glutamate
release.

## Key facts

- **NIH application ID:** 9888453
- **Project number:** 5R21NS109668-02
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** JEFFREY D ERICKSON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,511
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888453

## Citation

> US National Institutes of Health, RePORTER application 9888453, Neuronal Activity-Regulated Glutamine Transporter (5R21NS109668-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9888453. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*