Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release in Caenorhabditis elegans.
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 Ca(2+)-activated K+ channel, and in unc-43, which encodes CaM-kinase II, and a gain-of-function mutation in egl-30, which encodes Gqalpha, 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.
Hawasli
Ammar H
AH
Department of Anesthesiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Saifee
Owais
O
Liu
Christine
C
Nonet
Michael L
ML
Crowder
C Michael
CM
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics; D004351:Drug Resistance; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010641:Phenotype; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000378:metabolism; D050765:Qa-SNARE Proteins; D013489:Suppression, Genetic; D050827:Syntaxin 1
D018685:Anesthetics, Inhalation; D000954:Antigens, Surface; D029742:Caenorhabditis elegans Proteins; C479565:Egl-30 protein, C elegans; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D024681:Potassium Channels, Calcium-Activated; D050765:Qa-SNARE Proteins; D050827:Syntaxin 1; C494845:slo-1 protein, C elegans; C494215:unc-64 protein, C elegans; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517679:unc-43 protein, C elegans; D043802:GTP-Binding Protein alpha Subunits, Gq-G11