# Molecular Mechanisms of Dense-Core Vesicle Release

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $237,000

## Abstract

The secretion of growth factors, peptide hormones, neuropeptides and biogenic amines from dense-core vesicles (DCVs)
in neurons and endocrine cells is a tightly-regulated event that drives physiological processes such as feeding, digestion,
energy storage, lactation, emotion and analgesia. Compromised DCV release is implicated in metabolic and neurological
disorders such as diabetes, eating disorders, depression, drug addiction, and Huntington’s disease. Yet the molecular
pathways that govern the release of DCVs, particularly in electrically excitable cells of the nervous and endocrine
systems, remain largely undefined. The objective of this proposal is to uncover molecular mechanisms that regulate DCV
secretion. Our central hypothesis is that the signaling pathways that govern DCV release vary between different classes
of cells, and between different populations of DCVs within the same cell, according to their selective expression and
trafficking of key, as of yet unidentified regulatory molecules. We further posit that, similar to small synaptic vesicles,
DCV release is tightly controlled by neuromodulatory signaling through G protein-coupled receptors (GPCRs). Our
innovative hypothesis challenges the existing paradigm that focuses exclusively on intracellular calcium as the primary
molecular determinant of DCV release. The discovery of diverse release mechanisms will provide a new understanding
for long-standing questions surrounding the challenges associated with evoking neuropeptide secretion. We will test our
hypothesis by addressing the following key knowledge gaps: 1) an understanding of the neural activity patterns and wide
range of intracellular calcium concentrations that drive DCV release in different neuron classes, 2) and understanding of
how neuromodulatory biochemical signaling can adjust the activity and/or calcium requirements for release, 3)
elucidation of endogenous GPCRs that can carry out this novel form of neuromodulatory cross-talk, 4) elucidation of the
diverse protein machineries associated with DCVs containing different cargoes in different cell classes. The proposed
research builds on 1) our recent establishment of several assays for monitoring the actions of tachykinin and opioid
neuropeptides in the striatum, 2) our recent discovery of diverse conditions for driving endogenous tachykinin and
opioid neuropeptide release, 3) our successful development of photoactivatable peptides for mimicking, and thus
calibrating, spatiotemporal aspects of endogenous release, and 4) the recent development of optical sensors that report
peptide release in brain tissue. Uncovering the general principles that govern DCV release will establish new connections
between intercellular and intracellular signaling pathways and reveal how they are integrated at the molecular level in
numerous biological systems that transmit information via DCV secretion. In the long term, we anticipate that the
unique signaling pathways uncovered can be exploi...

## Key facts

- **NIH application ID:** 10135663
- **Project number:** 3R35GM133802-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Matthew R. Banghart
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,000
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135663

## Citation

> US National Institutes of Health, RePORTER application 10135663, Molecular Mechanisms of Dense-Core Vesicle Release (3R35GM133802-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10135663. Licensed CC0.

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