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Title: Molecular mechanisms of synaptic vesicle exocytosis
Author: Hu, K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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Release of neurotransmitter occurs when synaptic vesicles fuse with the plasma membrane. This neuronal exocytosis is triggered by calcium and requires three SNARE (soluble-ethylmaleimide-sensitive factor attachment protein receptor) proteins. Neuronal SNARE proteins form a parallel four-helix bundle that is thought to drive the fusion of opposing membranes. As formation of this SNARE complex in solution does not require calcium, it is not clear what function calcium has in triggering SNARE-mediated membrane fusion. The present study demonstrates that whereas syntaxin and SNAP-25 in target membranes are freely available for SNARE complex formation, availability of synaptobrevin on synaptic vesicles is very limited. Calcium at micromolar concentrations triggers SNARE complex formation and fusion between synaptic vesicles and reconstituted target membranes. The data suggest a mechanism in which calcium-triggered membrane apposition enables syntaxin and SNAP-25 to engage synaptobrevin, leading to membrane fusion. Modulation of neurotransmitter release probability by regulatory factors likely affects the transfer of information within the nervous system. Although many of the rules governing release probabilities at the synapse have been discovered, their molecular basis is still under investigation. I analyse stimulus-evoked probabilistic assembly of the SNARE fusion machinery and show that a simple SNARE-based mechanism can account quantitatively for the classical binomial behaviour of stochastic neurotransmitter release. The analysis highlights how the machinery that performs fusion may also contribute to the rich variety of synaptic responses. Complexin is a neuronal cytosolic protein that acts as a positive regulator of synaptic vesicle exocytosis. Complexin binds selectively to the neuronal SNARE complex, but how this promotes exocytosis remains unknown. Here I show that the action of complexin on SNARE complex depends strictly on the transmembrane regions of syntaxin and synaptobrevin. The data indicate that complexin may facilitate neuronal exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions which reside in opposing membranes prior to fusion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available