# Mechanisms of calcium-dependent neurotransmitter release in health and disease

> **NIH NIH F30** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $50,520

## Abstract

PROJECT ABSTRACT/SUMMARY
All known cognitive, affective, and related behavioral processes rely on circuits formed by neuronal ensembles.
High-fidelity communication between neurons requires the regulated release of neurotransmitters, which are
usually contained in membrane-enclosed vesicles at presynaptic terminals. In most neurons, Ca2+ influx from
voltage-gated channels acts upon presynaptic proteins to trigger fusion of these vesicles with the plasma
membrane. The principal Ca2+ sensors for fast neurotransmitter release are members of the Synaptotagmin
(Syt) families, principally Syt-1. De novo missense mutations in Syt-1 have been found in human patients with
profound global developmental delays, underscoring the essential role this protein plays in brain function. A
pair of closely-related proteins, Doc2α and Doc2β (collectively “Doc2”), have similar structural features but
trigger release on a slower timescale as compared to Syt-1. Both Syt-1 and Doc2 contain tandem C2 domains
that interact with membranes in a Ca2+-dependent fashion. But despite intensive study, it remains unclear how
Syt-1 and Doc2 act upon presynaptic membranes and other proteins to trigger fusion. Candidate mechanisms
include (1) the action of Syt-1/Doc2 on presynaptic membranes, and (2) direct interactions with soluble N-
ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, which catalyze membrane
fusion.
This proposal seeks to address major unanswered questions about the Syt-1/Doc2—membrane and Syt-
1/Doc2—SNARE interactions that enable fast, Ca2+-triggered membrane fusion. Using a set of biophysical
approaches, these experiments will define how SNAREs and physiologic phospholipids cooperate to shape the
Syt-1/Doc2—membrane interface before, during, and after membrane fusion. Syt-1 mutations from human
patients, two of which have not yet been described in the literature, will be studied using a combination of
biophysical approaches and high-speed imaging of glutamate release in live neurons. By defining critical
structure-function relationships in Syt-1, these results will establish a biophysical and physiologic basis for how
Syt-1 mutations cause disease in human patients. Together, the proposed experiments stand to significantly
deepen our mechanistic understanding of neurotransmission in health and disease.

## Key facts

- **NIH application ID:** 9918992
- **Project number:** 5F30MH116580-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Mazdak Bradberry
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918992

## Citation

> US National Institutes of Health, RePORTER application 9918992, Mechanisms of calcium-dependent neurotransmitter release in health and disease (5F30MH116580-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918992. Licensed CC0.

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