# Molecular Mechanism and Regulation of Asynchronous Release

> **NIH NIH R00** · VANDERBILT UNIVERSITY · 2021 · $239,585

## Abstract

Project Summary/Abstract
Neurotransmitter release is influenced by drugs, and certain mental disorders such as depression, but the details are
unclear. It is mediated by the SNARE complex, complexin (Cpx), synaptotagmin (Syt), and other proteins. Asynchronous
release is a mode of neurotransmitter release. It has received increasing attention as it may generate or compensate
abnormal neural activities, and play critical role in pre-synaptic plasticity. While most neuronal communication relies
upon synchronous release triggered by the Ca2+ sensors Syt1, 2 and 9 (collectively called “fast Syts”). Asynchronous
release has a longer, variable delay after an action potential or series of action potentials, and it is mediated by the Ca2+
sensor Syt7. Fast Syts and Syt7 share a similar domain structure and a high degree of homology in their Ca2+-binding C2A
and C2B domains. Recently I have identified the "primary" SNARE-Syt1 interface between Syt1 C2B domain and the
SNARE complex, revealing the "primary" interface is specific for synchronous release. In contrast, Syt7 does not form a
similar "primary" interface. These results raise the following questions: 1) how does Syt7's cooperate with SNAREs and
Cpx to trigger "delayed" asynchronous release; 2) what is the difference between fast Syts and Syt7 that gives rise to the
different modes of neurotransmitter release; 3) how is asynchronous release regulated by Syts and Ca2+. The overall goal
of this proposal is the elucidation of the molecular mechanism and regulation of asynchronous release. The proposed
study will examine how Syt7 mediates asynchronous release in cultured cortical neurons and brain slices from Syt1/7
double knockout mice with re-introduction of mutates designed based on sequence analysis and a newly solved crystal
structure of SNARE-Cpx-Syt1 complex. Finally, I will reveal the interaction among Syt1/7, Cpx, SNARE complex and
membrane, and investigate the regulation of asynchronous release by Syt1, Syt7 and Ca2+. Combined with my work on
synchronous release, such results are expected to provide a better understanding of the roles of neurotransmitter release in
neural activity and mental disorders, may lead to new therapeutics for the prevention and treatment of a variety of mental
disorders. In addition, the results are also expected to vertically advance the understanding of pre-synaptic plasticity
which is believed to be related to memory, learning, and behavior, as well as fundamentally advance the field of
neuroscience. My long-term career goal is to lead a world-class laboratory in the forefront of synaptic physiology. I intend
to use techniques in structural biology, single molecule spectroscopy and imaging, as well as key techniques in
neuroscience as investigation tools. To complement my knowledge of structural biology acquired during my PhD, I will
carry out the mentored phase of this Award as a postdoctoral Research Fellow in the laboratories of Drs. Axel Brunger
and Thomas Südho...

## Key facts

- **NIH application ID:** 10085261
- **Project number:** 5R00MH113764-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Qiangjun Zhou
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $239,585
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085261

## Citation

> US National Institutes of Health, RePORTER application 10085261, Molecular Mechanism and Regulation of Asynchronous Release (5R00MH113764-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085261. Licensed CC0.

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