# The mechanism of allosteric modulation of glutamate transporters

> **NIH NIH R01** · DREXEL UNIVERSITY · 2024 · $563,474

## Abstract

Abstract
Excitatory amino acid transporters (EAATs) remove synaptically released glutamate and maintain extracellular
glutamate concentrations below neurotoxic levels. Particularly the glial glutamate transporter EAAT2 plays a
major role in glutamate clearance in synaptic clefts. Removal of excess cellular glutamate is strongly implicated
as a clinically relevant means to treat neurodegenerative diseases where excitotoxicity due to excess glutamate
contributes to neuronal injury and death.
We have designed a unique research program to understand the molecular mechanisms of allosteric modulation
of glutamate transporters by recently discovered small-compound molecules, including long-sought activators of
transport. To reach this goal, we will obtain and integrate multidisciplinary knowledge of the transport function,
3D structures, and single-molecule dynamics of the transporters and their complexes with the allosteric
compounds. In turn, this knowledge will aid understanding the basic membrane transport mechanisms of the
most important excitatory neurotransmitter in the human brain.
We will pursue the following aims:
Aim 1: Elucidate the molecular determinants within the human EAATs that are important for allosteric
modulator activity. We will use functional studies and computational approaches to define the allosteric site
within EAAT2 that mediate the effects of the compounds.
Aim 2: Determine the structures of human EAATs in complex with allosteric modulators. We will determine
the three-dimensional structures of EAATs in complex with positive and negative allosteric modulators to unravel
the atomic details of their coordination.
Aim 3: Establish whether allosteric modulators modulate the function of EAATs though altering the rates
of conformational transitions underlying transport. We will examine the conformational dynamics and its
modulation by allosteric modulators using single-molecule FRET and other spectroscopic techniques and couple
these studies with single-vesicle/single-transporter assays to determine the effects of allosteric modulators on
turnover rates and the timing of transport cycles.
IMPACT: Information generated in this research program will open new avenues for drug discovery as these
transporters serve as important drug targets for many severe debilitating CNS conditions, such as traumatic
brain injury, stroke, epilepsy, ALS and neuropathic pain, that collectively affect nearly 5% of the American
population.

## Key facts

- **NIH application ID:** 10764903
- **Project number:** 5R01NS111767-05
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Olga Boudker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,474
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764903

## Citation

> US National Institutes of Health, RePORTER application 10764903, The mechanism of allosteric modulation of glutamate transporters (5R01NS111767-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10764903. Licensed CC0.

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