Mutations conferring new patterns of sensitivity to volatile anesthetics in Caenorhabditis elegans.
BACKGROUND
We previously described the use of the nematode Caenorabditis elegans as a genetic model for studying the mechanism of action of volatile anesthetics. All previous strains of C. elegans with altered responses to anesthetics have been identified by screening the response to halothane. The current study was designed to identify classes of mutations by screening for alterations in sensitivity to enflurane, isoflurane, and diethylether.


METHODS
Nematodes were mutated and the resulting mutant strains were screened for immobility in low doses of enflurane, isoflurane, or diethylether. Concentrations of halothane, enflurane, isoflurane, and diethylether that anesthetized 50% of the animals were determined in all mutations. Interactions of some new mutations with previously identified mutations were determined by construction of double mutants.


RESULTS
Mutations in six genes were identified and were divided into two classes. One class primarily affected sensitivity to enflurane and isoflurane; a second class affected sensitivity to all of the volatile anesthetics studied. The effects of the latter group dominated the effects of previously identified mutations.


CONCLUSIONS
The interaction of these mutations indicates that multiple sites of anesthetic action exist and that there are at least three such sites. A pathway for control of sensitivity to volatile anesthetics is proposed.
Morgan
P G
PG
Department of Anesthesiology, University Hospitals of Cleveland, Ohio.
Sedensky
M M
MM
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D002874:Chromosome Mapping; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000235:genetics*; D004737:Enflurane / Q000494:pharmacology; D004986:Ether / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008957:Models, Genetic; D009154:Mutation
D000777:Anesthetics; D004986:Ether; D004737:Enflurane; D007530:Isoflurane; D006221:Halothane