# Structure and Function of Neurotransmitter Transporters

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $466,529

## Abstract

Summary
Chemical neurotransmission forms the basis for most neurotransmission and involves the
release of neurotransmitter from a presynaptic neuron, the detection of the transmitter on
receptors located on both post and presynaptic neurons, and the ‘uptake’ of the transmitter
by neurotransmitter sodium symporters (NSSs), thus quenching the neurotransmitter
signal. NSSs are sodium-coupled membrane transport proteins that harness the pre-
existing ion gradient to ‘pump’ neurotransmitters into cells and ‘up’ their concentration
gradient. The removal of transmitter from the synaptic cleft and surrounding extracellular
spaces is crucial to neurotransmission and dysfunction of NSSs underpins multiple
neurological conditions. Moreover, there are many important therapeutic agents, as well as
illicit substances, that target NSSs, including antidepressants, anti-anxiety medications,
and amphetamines and cocaine. The goals of the research described in this grant
application are to further our understanding of the biochemical mechanism of NSS
function, to better understand how small molecule therapeutic agents and illicit substances
interact with NSSs, and to provide structure-based understanding of the consequences of
selected naturally occurring mutations in NSS genes. The major focus of the research is
to study the human serotonin and dopamine transporters using single particle cryo-
electron microscopy (cryo-EM) in combination with complementary biochemical,
biophysical and computational methods. We are particularly interested in understanding,
at the level of molecular detail, how newly discovered small molecules inhibit NSSs via
binding to a novel binding site and how these small molecules block isomerization of the
transporter to the inward facing conformations required to release transmitter. Moreover,
we will elucidate the underpinning molecular interactions between key small molecules and
the dopamine transporter to understand the principles of affinity and specificity, and we will
also examine how posttranslational modifications, such as phosphorylation, affect
transporter conformation. The results from our studies will unveil new small molecule
binding sites and cognate small molecules, illuminate structural underpinnings of
phosphorylation, and explore the conformational landscape of NSSs in distinct, ligand and
ion bound states. Our studies will not only inform the immediate NSS field, but because
NSSs are paradigm integral membrane transporter proteins, our studies will enlighten the
larger field of membrane transport.

## Key facts

- **NIH application ID:** 10981684
- **Project number:** 2R01MH070039-22
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** James E Gouaux
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,529
- **Award type:** 2
- **Project period:** 2004-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981684

## Citation

> US National Institutes of Health, RePORTER application 10981684, Structure and Function of Neurotransmitter Transporters (2R01MH070039-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981684. Licensed CC0.

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