Synaptic transmission is key for interneuronal communication and is mediated by neurotransmitters that are released 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. This research is also relevant to cell biology in general because of its importance to understand intracellular membrane fusion, and to other diseases that arise from defects of regulated secretion, which plays a wide variety of physiological functions such as control of heart rate, blood pressure or insulin release. Release is governed by a complex protein machinery that includes 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. Our research has recently identified multiple weak interactions between the components of the release machinery that could play critical roles because they can catalyze structural rearrangements and can be enhanced by cooperativity. Elucidating the structural basis for these interactions is essential to take a quantum leap and gain a true understanding of the mechanism of release. Moreover, the influence of membranes on these interactions needs to be characterized, ideally in the context of trans-SNARE complexes bridging two apposed membranes. The research proposed in this application is designed to address these questions and will test emerging models for the functions of these proteins, with the goal of developing a detailed picture of the mechanism of release that integrates all their functions. This research involves an interdisciplinary approach integrating structural studies at atomic resolution, biochemical experiments, reconstitution assays and electrophysiological analyses of neurotransmitter release in neurons performed by collaborators.
Four specific aims are proposed that focus on: 1. Munc18-1-SNARE interactions;2. Munc13-1 function in fusion;3. Dual roles of complexin-1;and 4. Reconstituting 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 the diverse diseases mentioned above.

Public Health Relevance

The research proposed in this application will yield key insights into fundamental molecular mechanisms that underlie synaptic transmission, a process that mediates communication between neurons. This knowledge is critical to understand how the brain and the nervous system in general function. Moreover, since many neurological disorders are treated with drugs that alter synaptic transmission, this research is expected to provide crucial clues for the development of novel strategies to understand and treat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037200-16
Application #
8429396
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
1997-12-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
16
Fiscal Year
2013
Total Cost
$443,408
Indirect Cost
$164,535
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
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
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
Kaeser, Pascal S; Deng, Lunbin; Wang, Yun et al. (2011) RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell 144:282-95
Li, Wei; Ma, Cong; Guan, Rong et al. (2011) The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors. Structure 19:1443-55
Xu, Yi; Seven, Alpay B; Su, Lijing et al. (2011) Membrane bridging and hemifusion by denaturated Munc18. PLoS One 6:e22012
Brewer, Kyle D; Li, Wei; Horne, Bethany Erin et al. (2011) Reluctance to membrane binding enables accessibility of the synaptobrevin SNARE motif for SNARE complex formation. Proc Natl Acad Sci U S A 108:12723-8
Sudhof, Thomas C; Rizo, Josep (2011) Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 3:
Ma, Cong; Li, Wei; Xu, Yibin et al. (2011) Munc13 mediates the transition from the closed syntaxin-Munc18 complex to the SNARE complex. Nat Struct Mol Biol 18:542-9
Citri, Ami; Bhattacharyya, Samarjit; Ma, Cong et al. (2010) Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression. J Neurosci 30:16437-52
Xue, Mingshan; Craig, Timothy K; Xu, Junjie et al. (2010) Binding of the complexin N terminus to the SNARE complex potentiates synaptic-vesicle fusogenicity. Nat Struct Mol Biol 17:568-75

Showing the most recent 10 out of 41 publications