Open AccessA microbial metabolite synergizes with endogenous serotonin to trigger C. elegans reproductive behavior
Author(s) -
Yen-Chih Chen,
Mohammad R. Seyedsayamdost,
Niels Ringstad
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2017918117
Subject(s) - neurochemical , caenorhabditis elegans , metabolite , neuroscience , psychopharmacology , serotonin , biology , signal transduction , dopamine , cell signaling , pharmacology , microbiology and biotechnology , biochemistry , receptor , gene
Natural products are a major source of small-molecule therapeutics, including those that target the nervous system. We have used a simple serotonin-dependent behavior of the roundworm Caenorhabditis elegans , egg laying, to perform a behavior-based screen for natural products that affect serotonin signaling. Our screen yielded agonists of G protein-coupled serotonin receptors, protein kinase C agonists, and a microbial metabolite not previously known to interact with serotonin signaling pathways: the disulfide-bridged 2,5-diketopiperazine gliotoxin. Effects of gliotoxin on egg-laying behavior required the G protein-coupled serotonin receptors SER-1 and SER-7, and the G q ortholog EGL-30. Furthermore, mutants lacking serotonergic neurons and mutants that cannot synthesize serotonin were profoundly resistant to gliotoxin. Exogenous serotonin restored their sensitivity to gliotoxin, indicating that this compound synergizes with endogenous serotonin to elicit behavior. These data show that a microbial metabolite with no structural similarity to known serotonergic agonists potentiates an endogenous serotonin signal to affect behavior. Based on this study, we suggest that microbial metabolites are a rich source of functionally novel neuroactive molecules.