Tyramine modulates the systemic stress response by stimulating the release of intestinal insulin like-peptides (ILPs)

Abstract

Multicellular organisms trigger a complex and coordinated response against systemic stress. We have recently shown that in C. elegans, the neural stress-hormone tyramine supplies a state-dependent neural switch between acute flight- and longterm environmental-stress responses (De Rosa et al, 2019). Tyramine release during the flight response, stimulates the DAF-2/ Insulin/IGF-1 signaling (IIS) pathway and precludes the nuclear translocation of the DAF-16/FOXO transcription factor through the activation of an adrenergic-like receptor TYRA-3 in the intestine. We hypothesize that tyramine stimulates the release of agonist ILPs from the intestine which acts as an autocrine and/or paracrine signal to systemically activate the DAF-2/IIS pathway. To test this hypothesis we are screening ILPs mutants for their resistance to environmental stressors (oxidative and thermal stress). The C. elegans genome encodes 40 ILPs, 28 of which expressed in the intestine. We performed a screening of intestinal peptides described as strong DAF-2 agonist, by silencing individual intestinal ILPs and testing worm resistance to environmental stressors (oxidative and thermal stress). Thus, so far we found that ins-3 and ins-7 mutants are resistant to environmental stress, like tyramine-deficient and tyra-3 mutants. We are further testing whether tyramine directly stimulates the release of these ILPs from the intestine through a Gq-protein mediated signaling pathway. These studies will provide insight into how a neurohormone coordinates systemic cellular stress responses