Cellular mechanisms of peptidergic signaling

Project Summary The secretion of growth factors, peptide hormones, neuropeptides and biogenic amines from neurons and endocrine cells is a tightly-regulated event that drives physiological processes such as feeding, digestion, energy storage, lactation, emotion and analgesia. Compromised peptide transmitter signaling is implicated in metabolic and neurological disorders such as diabetes, eating disorders, depression, drug addiction, and Huntington’s disease. Yet, the molecular pathways that govern the release of peptide transmitters, particularly in electrically excitable cells of the nervous and endocrine systems, remain largely undefined. The objective of this proposal is to uncover cellular mechanisms that regulate peptide transmitter secretion from mammalian central neurons. Our central hypothesis is that peptide release from neurons is governed by diverse mechanisms in a cell type- specific manner. We further posit that, similar to small synaptic vesicles, peptide release is tightly controlled by neuromodulatory signaling through G protein-coupled receptors (GPCRs). Our innovative hypothesis challenges the existing paradigm that focuses exclusively on intracellular calcium as the primary molecular determinant of peptide release. The discovery of diverse release mechanisms will address long-standing questions surrounding the challenges associated with evoking neuropeptide secretion. Our work will increase our understanding of the neurophysiological events that drive and regulate peptide release in different neuron classes. The proposed research builds on our recent establishment of several assays for monitoring the actions of neuropeptides in the striatum and our successful development of diverse photoactivatable peptides for mimicking, and thus calibrating, spatiotemporal aspects of endogenous release. Uncovering the general principles that govern peptide secretion from neurons will establish new connections between intercellular and intracellular signaling pathways and reveal how they are integrated at the molecular level in numerous biological systems that transmit information via peptide signaling. In the long term, we anticipate that the new signaling pathways uncovered might be exploited to treat metabolic diseases, psychological disorders and neurodegenerative disease, and pain. By uncovering new connections between signaling pathways that are fundamental to human physiology in both health and disease, the findings of this work will likely impact numerous scientific fields, including cancer, cardiology, development, gastroenterology, and neuroscience.