Synaptic transmission in the brain is initiated by neurotransmitter release, which is mediated by synaptic vesicle exocytosis. Insights into the mechanisms of neurotransmitter release and its regulation are essential for understanding how the brain processes information, and how synaptic transmission is affected in diseases such as Parkinson's disease, Alzheimer's disease, and drug addiction. Release is governed by a complex protein machinery that includes as central components proteins with homologues in most types of intracellular membrane fusion such as the SNARE proteins and munc18-1. In addition, several proteins such as munc13-1 and complexins play critical roles that are specialized for the tight spatial and temporal regulatory requirements of neurotransmitter release. While the research performed under this grant and studies from other laboratories have yielded key insights into how these proteins function, the mechanism of release is still unclear and fundamental questions remain unanswered. The research proposed in this application is designed to build on this success and on crucial findings made in preliminary experiments that suggest novel interactions between these key components and new hypotheses on how they function. These include an interaction between munc18-1 and the SNAREs that suggest a novel model for the core of the fusion machinery, and a munc18-1/munc13-1 interaction that suggest a novel mechanism for the priming step that leaves synaptic vesicles ready for neurotransmitter release. This research involves an interdisciplinary approach integrating structural studies at atomic resolution, biochemical experiments, reconstitution assays and electrophysiological analyses of neurotransmitter release in neurons.
Four specific aims are proposed that focus on: 1. Munc 18-1/SNARE interactions;2. Mechanisms of munc13-1 action and its regulation;3. Complexin/SNARE interactions;and 4. Reconstitution of basic steps of neurotransmitter release. The results of this research will not only be important to understand the mechanisms of neurotransmitter release and membrane fusion in general, but will also have an impact in the design of therapies for brain disorders that involve changes in synaptic transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037200-13
Application #
7807057
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (04))
Program Officer
Talley, Edmund M
Project Start
1997-12-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
13
Fiscal Year
2010
Total Cost
$405,638
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Park, Seungmee; Bin, Na-Ryum; Yu, Bin et al. (2017) UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans. J Neurosci 37:8797-8815
Xu, Junjie; Camacho, Marcial; Xu, Yibin et al. (2017) Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. Elife 6:
Pan, Yun-Zu; Quade, Bradley; Brewer, Kyle D et al. (2016) Sequence-specific assignment of methyl groups from the neuronal SNARE complex using lanthanide-induced pseudocontact shifts. J Biomol NMR 66:281-293
Liu, Xiaoxia; Seven, Alpay Burak; Camacho, Marcial et al. (2016) Functional synergy between the Munc13 C-terminal C1 and C2 domains. Elife 5:
Yang, Xiaoyu; Wang, Shen; Sheng, Yi et al. (2015) Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat Struct Mol Biol 22:547-54
Rizo, Josep; Xu, Junjie (2015) The Synaptic Vesicle Release Machinery. Annu Rev Biophys 44:339-67
Trimbuch, Thorsten; Xu, Junjie; Flaherty, David et al. (2014) Re-examining how complexin inhibits neurotransmitter release. Elife 3:e02391
Gonzalez, Paulina; da Costa, Viviana C P; Hyde, Kimberly et al. (2014) Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease. Metallomics 6:2072-82
Rizo, Josep; Xu, Junjie (2013) Synaptic vesicle fusion without SNARE transmembrane regions. Dev Cell 27:124-126
Ma, Cong; Su, Lijing; Seven, Alpay B et al. (2013) Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339:421-5

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