Before Ca 2+ dependent neurotransmitter release from the presynapse can be achieved, vesicle have to traffic to the active zone and prime to a fusion competent state. Vesicle priming is 1 of the key processes determining the efficiency of the synaptic transmission and plasticity. Central to the vesicle priming step is the controlled assembly of the synaptic trimeric SNARE protein complex consisting of Syntaxin 1, SNAP-25 and Synaptobrevin. Syntaxin 1 is the only synaptic SNARE protein that contains a regulatory, putative autoinhibitory domain, and it is thought that the closed, autoinhibitory conformation has to be opened before SNARE assembly can proceed. The putative function of the essential priming factors Munc13-1 and -2 is to catalyze this conformational change. In addition, Munc13 isoforms may dynamically regulate vesicle priming in response to presynaptic activity. Munc13-1 dependent synapses depress during trains of action potential, and Munc13-2 dependent synapses augment.
The aims of this proposal is to functionally analyze the role of the conformational switch in Syntaxin 1 by studying synaptic transmission from murine neurons that express a mutation in the endogenous Syntaxin 1 protein locked in the open conformation. Second, we aim to analyze the molecular mechanism of Munc13 function by systematic analysis of the role of Munc13 domains in vesicle priming using a gain of function rescue approach. We will finally analyze how Munc13 isoforms regulate short-term plasticity in individual synapses, and how Munc13 dependent depression and augmentation control information flow and synaptic plasticity in the central nervous system. A molecular description of the the 2 key molecules involved in vesicle priming will aid the design of therapeutic drugs manipulating the efficacy and plasticity of presynaptic function. Moreover, a detailed knowledge of the mechanisms of neurotransmitter release is critical for the understanding of ethnology and treatment of neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051262-05
Application #
7586140
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$328,901
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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