# Molecular Mechanisms of VMAT2 Function

> **NIH NIH R36** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $52,800

## Abstract

Abstract
Monoaminergic signaling controls many aspects of human physiology, including autonomic responses,
movement, and emotion. The vesicular monoamine transporter 2 (VMAT2) is the primary transporter
responsible for loading monoaminergic neurotransmitters into synaptic vesicles (SVs) in the central nervous
system. Due to this role, dysregulation of VMAT2 can result in a variety of neuropsychiatric disorders including
Parkinson’s disease, depression, and drug addiction. Clinically, VMAT2 is targeted by inhibitors tetrabenazine
(TBZ) and reserpine (RES) for the treatment of Huntington’s disease and hypertension respectively.
Amphetamine is an addictive drug that is known to act on VMAT2 to cause vesicle deacidification and eventual
release of neurotransmitters from SVs and into the cytosol. These neurotransmitters are then effluxed into the
synapse from the pre-synaptic neuron where they can bind to receptors and elicit downstream effects. Despite
VMAT2’s role in these processes, little is known mechanistically about how VMAT2 functions to load
neurotransmitters into vesicles, and how amphetamine causes release of neurotransmitters from those
vesicles through its interaction with VMAT2. This represents a critical knowledge gap, and understanding these
processes will lead to improved means of combating diseases of VMAT2 dysregulation and the deadly effects
of amphetamine abuse. To tackle these questions, we will perform detailed structure-function analysis of
VMAT2 to reveal structural changes undergone by the transporter throughout the transport cycle, identify the
mechanism of substrate recognition, and how amphetamine acts on VMAT2 to cause neurotransmitter release.
To this end, we will pursue two specific aims: 1) Determine the basis of reserpine inhibition; and 2) understand
the molecular mechanisms of VMAT2 substrate transport and amphetamine action. Our anticipated results will
deepen our understanding of SV loading, and illuminate the mechanism of amphetamine action. They will
further provide foundational knowledge about how membrane transporters recognize and transport substrates
that will be applicable to related major facilitator family proteins. These studies will guide the development of
novel treatments with fewer side effects and greater specificity, and provide new avenues for the treatment of
drug abuse.

## Key facts

- **NIH application ID:** 10947390
- **Project number:** 1R36DA061055-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Michael P Dalton
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,800
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947390

## Citation

> US National Institutes of Health, RePORTER application 10947390, Molecular Mechanisms of VMAT2 Function (1R36DA061055-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10947390. Licensed CC0.

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