# Structure and Function of Neurotransmitter Transporters

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $385,626

## Abstract

Signaling between neurons is accomplished, in large part, by chemical neurotransmission which 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). NSSs are sodium-coupled membrane transport proteins that harness the pre-
existing ion gradient to `pump' neurotransmitters into cells, up the concentration gradient. Because the
removal of transmitter from the synaptic cleft and surrounding extracellular spaces is crucial to
neurotransmission, dysfunction of NSSs underpins a number of neurological conditions and there are many
important therapeutic agents, as well as illicit substances, that target NSSs, including antidepressants, anti-
anxiety medications, amphetamines and cocaine, as examples. 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 will be to study the human serotonin and dopamine transporters
using the structural methods of single particle cryo electron microscopy (cryo-EM) and x-ray crystallography
in combination with complementary biochemical, biophysical and computational methods. We are
particularly interested in understanding, at the level of molecular detail, how NSSs isomerize from the
outward facing conformations required to bind neurotransmitter to the inward facing conformations that are
required to release transmitter. Moreover, we will elucidate the molecular contacts that underpin the
interactions between key small molecules and NSSs to understand the principles of affinity and specificity,
and we will also examine how key posttranslational modifications, such as phosphorylation, affect
transporter conformation. The results from our studies will allow for a comprehensive understanding of the
relationships between NSS structure and function and they will also provide an underpinning for further
structure-based design of small molecules with potentially useful properties. Our studies will not only inform
the immediate NSS field but, because NSSs are paradigm integral membrane transporter proteins, our
studies will enlighten the much larger field of membrane transport.

## Key facts

- **NIH application ID:** 9932254
- **Project number:** 5R01MH070039-18
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** James E Gouaux
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,626
- **Award type:** 5
- **Project period:** 2004-07-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932254

## Citation

> US National Institutes of Health, RePORTER application 9932254, Structure and Function of Neurotransmitter Transporters (5R01MH070039-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932254. Licensed CC0.

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