title: Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans.
abstract: Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Pedro
authors.initials: P
authors.lastname: Reis Rodrigues
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Tiffany K
authors.initials: TK
authors.lastname: Kaul
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Jo-Hao
authors.initials: JH
authors.lastname: Ho
authors.affiliation: The Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Mark
authors.initials: M
authors.lastname: Lucanic
authors.affiliation: Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, Massachusetts 02115.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Burkewitz
authors.affiliation: Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, Massachusetts 02115.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110 Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Held
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida 33458 mgill@scripps.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Gill
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000220:Adaptation, Biological / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007814:Larva; D008024:Ligands; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000235:genetics* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D063387:Cannabinoid Receptor Antagonists; D007328:Insulin; D008024:Ligands; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D011985:Receptors, Serotonin; D016212:Transforming Growth Factor beta; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: C. elegans; dauer; synthetic cannabinoids