# Structural and functional investigations on synaptic vesicular transporters

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $523,387

## Abstract

PROJECT SUMMARY
Chemical neurotransmission, an essential component of neuronal communication in the brain, is facilitated by
specialized organelles known as synaptic vesicles. These vesicles mediate the release of neurotransmitters
across synapses. Transporters within the vesicles establish chemical and electrical gradients and load
neurotransmitters into the vesicles, ensuring efficient neurotransmitter release. Defects in these transporters
often associate with neurological diseases, including epilepsy, neurodegeneration, and mental illness. Despite
their importance, many of these transporters remain understudied at a molecular level. One of the most
abundant membrane proteins in synaptic vesicles is synaptic vesicle glycoprotein 2 (SV2), a putative
transporter that is critical for normal synaptic function. Mutations in human SV2 lead to epilepsy and cognitive
impairment, and SV2 is a known target of commonly used antiepileptic medications. However, the precise
function of SV2 and how it mediates synaptic transmission remain largely unknown. Similarly, the mechanism
by which drugs targeting SV2 treat epilepsy is still elusive. We propose an integrated approach that combines
single-particle cryo-electron microscopy, in vivo and in vitro assays, and mass spectrometry to answer critical
questions about SV2: what is its substrate and how is it recognized? What is the nature of the translocation
pathway and how does SV2 transport the substrate? How do antiepileptic drugs regulate SV2? Our research
will significantly advance our understanding of the function and mechanisms of SV2 in synaptic biology, and
provide a strong foundation for developing more effective therapeutic interventions for epilepsy.

## Key facts

- **NIH application ID:** 10879977
- **Project number:** 1R01NS133147-01A1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Chia-Hsueh Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,387
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879977

## Citation

> US National Institutes of Health, RePORTER application 10879977, Structural and functional investigations on synaptic vesicular transporters (1R01NS133147-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879977. Licensed CC0.

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