A Caenorhabditis elegans pheromone antagonizes volatile anesthetic action through a go-coupled pathway.
Volatile anesthetics (VAs) disrupt nervous system function by an ill-defined mechanism with no known specific antagonists. During the course of characterizing the response of the nematode C. elegans to VAs, we discovered that a C. elegans pheromone antagonizes the VA halothane. Acute exposure to pheromone rendered wild-type C. elegans resistant to clinical concentrations of halothane, increasing the EC(50) from 0.43 +/- 0.03 to 0.90 +/- 0.02. C. elegans mutants that disrupt the function of sensory neurons required for the action of the previously characterized dauer pheromone blocked pheromone-induced resistance (Pir) to halothane. Pheromone preparations from loss-of-function mutants of daf-22, a gene required for dauer pheromone production, lacked the halothane-resistance activity, suggesting that dauer and Pir pheromone are identical. However, the pathways for pheromone's effects on dauer formation and VA action were not identical. Not all mutations that alter dauer formation affected the Pir phenotype. Further, mutations in genes not known to be involved in dauer formation completely blocked Pir, including those altering signaling through the G proteins Goalpha and Gqalpha. A model in which sensory neurons transduce the pheromone activity through antagonistic Go and Gq pathways, modulating VA action against neurotransmitter release machinery, is proposed.
van Swinderen
Bruno
B
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Metz
Laura B
LB
Shebester
Laynie D
LD
Crowder
C Michael
CM
D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D006221:Halothane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism; D010675:Pheromones / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D018685:Anesthetics, Inhalation; D018377:Neurotransmitter Agents; D010675:Pheromones; D017981:Receptors, Neurotransmitter; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D006221:Halothane