The goal of this project is to identify factors that regulate secretion of neuropeptides generally, and to determine how these secreted peptides regulate behavior. The motivation for this project is two-fold. First, insulin secretion, and its misregulation, plays a pivotal role in aging, diabetes, and obesity. Second, while a great deal has been learned about mechanisms regulating secretion of classical neurotransmitters, far less is known about those regulating secretion of neuropeptides and hormones. Classical neurotransmitters are packaged in synaptic vesicles (SVs), which are clustered at active zones. Neuropeptides are packaged into large dense core vesicles (DCVs), and are distributed throughout axons and dendrites. Secretion of SVs occurs at active zones, in a rapid, phasic manner in response to single action potentials. Secretion of DCVs occurs typically after trains of depolarization, fusion events occur far from active zones, and they occur relatively slowly following depolarization. Following exocytosis, the SV pool is rapidly reconstituted at nerve terminals by endocytic recycling of SV components, and refilling with neurotransmitters. By contrast, the releasable pool of DCVs must be reconstituted by anterograde transport of immature secretory granules from the soma. Relatively little is known about the biochemical basis for these differences. We propose to identify factors that are required for or that regulate DCV secretion, using C. elegans as a model system. In preliminary studies, we identify a neuropeptide that regulates arousal from a sleep-like state. Here we propose to determine how secretion of this peptide is regulated, and the mechanism by which this peptide causes arousal. These studies should provide new insights into the cellular mechanisms regulating secretion of neuropeptides sleep, and arousal.
This proposal describes a coherent set of genetic, molecular, and biophysical experiments designed to identify factors that differentially regulate secretion of classical neurotransmitters and neuropeptides, and how secreted peptides regulate sleep and arousal. These experiments may identify new potential targets for therapeutic intervention into diabetes, obesity, aging, and sleep disorders.
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