RRC ID 53268
Author Reis Rodrigues P, Kaul TK, Ho JH, Lucanic M, Burkewitz K, Mair WB, Held JM, Bohn LM, Gill MS.
Title Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans.
Journal G3 (Bethesda)
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.
Volume 6(6)
Pages 1695-705
Published 2016-6-1
DOI 10.1534/g3.116.026997
PII g3.116.026997
PMID 27172180
PMC PMC4889665
MeSH AMP-Activated Protein Kinases / metabolism Adaptation, Biological / drug effects Adaptation, Biological / genetics* Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Cannabinoid Receptor Antagonists / chemistry Cannabinoid Receptor Antagonists / pharmacology Glucose / metabolism Insulin / metabolism Larva Ligands Neurons / drug effects Neurons / metabolism Receptors, Cannabinoid / genetics* Receptors, Cannabinoid / metabolism* Receptors, G-Protein-Coupled / metabolism Receptors, Serotonin / metabolism Reproduction / drug effects Reproduction / genetics Signal Transduction / drug effects Transforming Growth Factor beta / metabolism
IF 2.781
Times Cited 5
C.elegans tm1946 tm2943 tm2416 tm2308