Characterization of the molecular mechanism underlying synaptic vesicle exocytosis.

摘要

During synaptic transmission, information is transferred from one neuron to another via a synapse. At a chemical synapse, synaptic transmission is mediated by the release of a chemical neurotransmitter from the presynaptic cell. The neurotransmitter diffuses across the synaptic cleft and activates cognate receptors on the postsynaptic cell. Therefore, at a chemical synapse, information transfer is dictated by the release of neurotransmitter from the presynaptic nerve terminal.; Synaptic vesicle exocytosis resides at the heart of neurotransmitter release. Synaptic vesicles are specialized membrane-enclosed organelles that contain a neurotransmitter. During exocytosis, synaptic vesicles associate, or dock, with the presynaptic plasma membrane, undergo a maturation step, termed priming, then fuse with the plasma membrane upon calcium signaling. Although synaptic vesicle exocytosis was first described over 20 years ago, a comprehensive model detailing the molecular mechanism of exocytosis remains elusive.; In this dissertation, a molecular and genetic characterization of synaptic vesicle exocytosis is described. Using the model organism Caenorhabditis elegans, we identify the presynaptic protein UNC-18 as a mediator of synaptic vesicle docking, the presynaptic proteins UNC-18, UNC-13 and RIM as mediators of priming and the novel presynaptic protein RIC-7 as a facilitator of synaptic vesicle exocytosis. Furthermore, we describe the molecular mechanism by which UNC-18, UNC-13 and RIM likely mediate synaptic vesicle priming, that is, by regulating the conformation of the t-SNARE protein syntaxin. Therefore, this dissertation provides a foundation for the construction of a model describing the molecular mechanism underlying synaptic vesicle exocytosis.