Investigation of the role of the G protein-coupled receptor FSHR-1 in multi-tissue control of neuromuscular signaling in normal and oxidative stress conditions - PROJECT SUMMARY/ABSTRACT Oxidative damage is a key contributor to many neurological and neurodegenerative disorders characterized by imbalances in synaptic transmission. Inter-tissue signaling is vital to stress-induced synaptic modulation in the face of such damage but is not fully understood. My long-term goal is to determine the molecular mechanisms controlling synaptic transmission in the presence and absence of oxidative stress. Recent work from my lab and others identified roles for the conserved G protein-coupled receptor (GPCR) FSHR-1 in regulating neuromuscular signaling and oxidative stress responses. FSHR-1 is the sole C. elegans homolog of a vertebrate glycoprotein (GP) hormone receptor family that controls various physiological and stress responses; misregulated signaling by these GP receptors is linked to neurological and neurodegenerative conditions, like depression and Alzheimer’s Disease. My lab previously found fshr-1-deficient C. elegans have neuromuscular defects exacerbated by oxidative stress. In the prior funding period, we showed FSHR-1 acts in the intestine, and likely also in glia, to cause muscle excitation via effects on cholinergic motor neurons and identified downstream effectors and GP ligands of intestinal FSHR-1. Yet, the inter-tissue mechanisms by which FSHR-1 regulates neuromuscular function from these distal tissues under normal or stress conditions are unknown. The objective of this proposal is to determine how FSHR-1 controls signaling at the C. elegans neuromuscular junction (NMJ) via activities in multiple cell types in differing oxidative stress conditions. My unpublished data indicate the conserved secretion regulator, HID-1, and insulin-like peptides (ILPs), INS-31 and INS-35, are required in the intestine for intestinal FSHR-1 to promote muscle excitation and also show FSHR-1 expression in a subset of astrocyte-like glia. Although FSHR-1 is required to promote motility in physiological conditions and in chronic oxidative stress, my data indicate FSHR-1 is needed to prevent motility under acute stress. My central hypothesis is that FSHR-1 acts downstream of - and β-GPs or other ligands in the intestine to promote intestinal ILP release via activity of the secretion regulator HID-1, and in IL socket (ILso) glia via other inter-tissue signals, to differentially regulate muscle excitation in chronic and acute oxidative stress. Aim 1 will use cell-specific gene expression/inhibition, fluorescence imaging, and behavior to define intestinal secretory pathways involved in FSHR-1’s effects on the NMJ. Aim 2 will use these methods plus cell-specific ablation to determine if and how FSHR-1 expressed in ILso glia regulates NMJ function. Aim 3 will use genetic epistasis and biochemistry to identify FSHR-1 ligands relevant for its NMJ effects in response to oxidative stress. This research is innovative in its plan to define multiple inter-tissue signaling pathways of a conserved GPCR that regulates synaptic transmission in varying physiological conditions. It is significant in identifying novel intestinal and glial roles for FSHR-1, which controls diverse biological processes across phylogeny, and thus may facilitate future treatments for synaptic dysfunction and oxidative stress, key contributors to aging and disease.
