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Genetics, Vol. 168, 831-843, October 2004, Copyright © 2004
doi:10.1534/genetics.104.030502
Resistance to Volatile Anesthetics by Mutations Enhancing Excitatory Neurotransmitter Release in Caenorhabditis elegans
Ammar H. Hawasli*,1,
Owais Saifee
,1,
Christine Liu*,
Michael L. Nonet and
C. Michael Crowder*,
,2
* Department of Anesthesiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110
Department of Molecular Biology and Pharmacology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110
Department of Anatomy and Neurobiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110
2 Corresponding author: Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110.
E-mail: crowderm{at}morpheus.wustl.edu
The molecular mechanisms whereby volatile general anesthetics (VAs) disrupt behavior remain undefined. In Caenorhabditis elegans mutations in the gene unc-64, which encodes the presynaptic protein syntaxin 1A, produce large allele-specific differences in VA sensitivity. UNC-64 syntaxin normally functions to mediate fusion of neurotransmitter vesicles with the presynaptic membrane. The precise role of syntaxin in the VA mechanism is as yet unclear, but a variety of results suggests that a protein interacting with syntaxin to regulate neurotransmitter release is essential for VA action in C. elegans. To identify additional proteins that function with syntaxin to control neurotransmitter release and VA action, we screened for suppressors of the phenotypes produced by unc-64 reduction of function. Loss-of-function mutations in slo-1, which encodes a Ca2+-activated K+ channel, and in unc-43, which encodes CaM-kinase II, and a gain-of-function mutation in egl-30, which encodes Gq
, were isolated as syntaxin suppressors. The slo-1 and egl-30 mutations conferred resistance to VAs, but unc-43 mutations did not. The effects of slo-1 and egl-30 on VA sensitivity can be explained by their actions upstream or parallel to syntaxin to increase the level of excitatory neurotransmitter release. These results strengthen the link between transmitter release and VA action.
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