Neurotransmitters are released from synapses by the fusion of synaptic vesicles with the plasma membrane. Synaptic vesicles must first dock to the plasma membrane, become primed for fusion, respond to calcium and fuse. Synaptic vesicle exocytosis is mediated in part by the SNARE proteins (syntaxin, synaptobrevin and SNAP-25), UNC-18 and the novel protein RIC-7. We will answer the following questions: What is the role of UNC-18 in exocytosis? 1. Is UNC-18 a direct regulator of docking? 2. Is UNC-18 required for the disassembly of the SNARE complex so that these proteins can function in subsequent rounds of exocytosis? 3. Does UNC-18 inhibit the formation of the SNARE complex by binding syntaxin? What is the role of SNARE proteins in exocytosis? 4. Is syntaxin required for docking? Is syntaxin required for fusion? 5. Is synaptobrevin required for docking? Is it required redundantly with synaptotagmin for docking? Is synaptobrevin required for fusion? Is it required redundantly with synaptotagmin to present synaptic vesicles to syntaxin? What is the role of RIC-7 in exocytosis? 6. RIC-7 is a novel protein required at the synapse. Is RIC-7 required for docking? Is RIC-7 required for priming, calcium sensing, or fusion? These studies will explore the molecular mechanisms of nervous system function. A molecular understanding of the synapse will provide us with the knowledge base that will be required to treat neurodegenerative disorders such as Alzheimer's Disease, to treat autoimmune diseases like Rasmussen's encephalitis, and genetic disorders of the nervous system.
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