Genetic evidence in Caenorhabditis elegans implicates a syntaxin-1A-binding protein as critical for presynaptic volatile anesthetic action

Abstract

Among the many cellular actions of volatile anesthetics (VAs), inhibition of neurotransmitter release is one of the least understood. The presynaptic release machinery has been proposed as a presynaptic VA target. We have found that the effects of clinical concentrations of VAs on locomotion in the nematode Caenorhabditis elegans are markedly reduced by mutation of the presynaptic SNARE protein syntaxin-1A. The syntaxin mutation results in a truncated syntaxin product along with reduced amounts of wild-type syntaxin. We hypothesize that the truncated mutant syntaxin functions to antagonize VA action on some unknown VA target, presumably by physically interacting with it. We have produced additional syntaxin truncation mutants, and their testing revealed that only the first two helical domains of the protein are necessary and sufficient for conferring VA resistance. This region of the protein is known to interact with only a few proteins, including N/P/Q/R-type calcium channels and UNC-13. Testing of a null mutant of the only known N/P/Q/R-type calcium channel showed that it was not VA resistant. These data implicate UNC-13 as the most likely mediator of VA sensitivity and could explain several puzzling observations about VA effects on vertebrate neurotransmitter release.