A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans

The molecular mechanisms underlying general anesthesia are unknown. For vol atile general anesthetics (VAs), indirect evidence for both lipid and prote in targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying th ese mechanisms, but genes strongly regulating sensitivity to clinical conce ntrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans, we found that a mutation in the neuro nal syntaxin gene dominantly conferred resistance to the VAs isoflurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-bi nding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33 fold range of sensitivities aas seen. Both the resistant and hypersen sitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assess ed by pharmacological criteria, halothane and isoflurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocke d by the resistant syntaxin mutation. A single gene mutation conferring hig h-lever resistance to VAs is inconsistent with nonspecific membrane-perturb ation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficac y against presynaptic targets that mediate anesthetic behavioral effects. S yntaxin and syntaxin-binding proteins are candidate anesthetic targets.