Genetics, Vol. 158, 643-655, June 2001, Copyright © 2001

Go{alpha} Regulates Volatile Anesthetic Action in Caenorhabditis elegans

Bruno van Swinderena, Laura B. Metza, Laynie D. Shebestera, Jane E. Mendelc, Paul W. Sternbergc, and C. Michael Crowdera,b
a Department of Anesthesiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine St. Louis, Missouri 63110
b Department of Molecular Biology/Pharmacology, Division of Biology and Biomedical Sciences, Washington University School of Medicine St. Louis, Missouri 63110
c Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, California 91125

Corresponding author: C. Michael Crowder, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110., crowderm{at}morpheus.wustl.edu (E-mail)

Communicating editor: B. J. MEYER

To identify genes controlling volatile anesthetic (VA) action, we have screened through existing Caenorhabditis elegans mutants and found that strains with a reduction in Go signaling are VA resistant. Loss-of-function mutants of the gene goa-1, which codes for the {alpha}-subunit of Go, have EC50s for the VA isoflurane of 1.7- to 2.4-fold that of wild type. Strains overexpressing egl-10, which codes for an RGS protein negatively regulating goa-1, are also isoflurane resistant. However, sensitivity to halothane, a structurally distinct VA, is differentially affected by Go pathway mutants. The RGS overexpressing strains, a goa-1 missense mutant found to carry a novel mutation near the GTP-binding domain, and eat-16(rf) mutants, which suppress goa-1(gf) mutations, are all halothane resistant; goa-1(null) mutants have wild-type sensitivities. Double mutant strains carrying mutations in both goa-1 and unc-64, which codes for a neuronal syntaxin previously found to regulate VA sensitivity, show that the syntaxin mutant phenotypes depend in part on goa-1 expression. Pharmacological assays using the cholinesterase inhibitor aldicarb suggest that VAs and GOA-1 similarly downregulate cholinergic neurotransmitter release in C. elegans. Thus, the mechanism of action of VAs in C. elegans is regulated by Go{alpha}, and presynaptic Go{alpha}-effectors are candidate VA molecular targets.




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