A novel functional cross-interaction between opioid and pheromone signaling may be involved in stress avoidance in Caenorhabditis elegans

Jun Young Park,Mi Cheong Cheong,Hyeon-Sook Koo,Jin-Young Cho,Young-Ki Paik

doi:10.1038/s41598-020-64567-3

Abstract

Upon sensing starvation stress, Caenorhabditis elegans larvae (L2d) elicit two seemingly opposing behaviors to escape from the stressful condition: food-seeking roaming mediated by the opioid peptide NLP-24 and dauer formation mediated by pheromones. Because opioid and pheromone signals both originate in ASI chemosensory neurons, we hypothesized that they might act sequentially or competitively to avoid starvation stress. Our data shows that NPR-17 opioid receptor signaling suppressed pheromone biosynthesis and the overexpression of opioid genes disturbed dauer formation. Likewise, DAF-37 pheromone receptor signaling negatively modulated nlp-24 expression in the ASI neurons. Under short-term starvation (STS, 3 h), both pheromone and opioid signaling were downregulated in gpa-3 mutants. Surprisingly, the gpa-3;nlp-24 double mutants exhibited much higher dauer formation than seen in either of the single mutants. Under long-term starvation (LTS, >24 h), the stress-activated SKN-1a downregulated opioid signaling and then enhanced dauer formation. Both insulin and serotonin stimulated opioid signaling, whereas NHR-69 suppressed opioid signaling. Thus, GPA-3 and SKN-1a are proposed to regulate cross-antagonistic interaction between opioids and pheromones in a cell-specific manner. These regulatory functions are suggested to be exerted via the selective interaction of GPA-3 with NPR-17 and site-specific SKN-1 binding to the promoter of nlp-24 to facilitate stress avoidance.

Highlights

Upon sensing starvation stress, Caenorhabditis elegans larvae (L2d) elicit two seemingly opposing behaviors to escape from the stressful condition: food-seeking roaming mediated by the opioid peptide NLP-24 and dauer formation mediated by pheromones
Nlp-24 expression was reduced during long-term starvation without exogenous pheromone, whereas nlp-24 expression was increased during short-term starvation (Fig. 1e,f)
These effects are presumably due to the long-term stress experienced by the control line during which nlp-24 expression may be reduced by endogenously synthesized pheromones in the body

Summary

Introduction

Caenorhabditis elegans larvae (L2d) elicit two seemingly opposing behaviors to escape from the stressful condition: food-seeking roaming mediated by the opioid peptide NLP-24 and dauer formation mediated by pheromones. Feeding via pharyngeal pumping ceases during when early C. elegans larvae enter the dauer stage, which is mainly mediated by pheromones[3,7,10,15,20] This interconnection between two behaviors (i.e., the cessation of feeding and entry into dauer) suggests that opioid and pheromone signaling pathways might initiate sequentially in the ASI neurons and mutually influence each other under starvation stress in C. elegans. The functional relationship of these two signaling pathways during stress avoidance and the mechanism by which pheromone-mediated dauer formation leads to the cessation of opioid-governed pharyngeal pumping are not completely understood Because both signaling pathways originate in ASI neurons, which likely produce a coherent common readout upon sensing starvation, we hypothesized the pathways might interact functionally during starvation stress (Fig. 1a). Our results could support the use of C. elegans as a convenient model organism for studying the molecular processes underlying opioid metabolism in vertebrate

Methods

Results

Conclusion