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Wednesday, October 22, 2008

UNC-18 Modulates Ethanol Sensitivity in Caenorhabditis elegans
in Press
, published online ahead of print October 15, 2008

Acute ethanol exposure affects the nervous system as a stimulant at low concentrations and a depressant at higher concentrations, eventually resulting in motor dysfunction and uncoordination.

A recent genetic study of two mice strains with varying ethanol preference indicated a correlation with a polymorphism (D216N) in the synaptic protein Munc18–1. Munc18–1 functions in exocytosis via a number of discrete interactions with the SNARE protein syntaxin-1.

We report that the mutation affects binding to syntaxin, but not through either a closed-conformation mode of interaction nor through binding to the syntaxin N-terminus. The D216N mutant instead has a specific impairment in binding the assembled SNARE complex. Furthermore, the mutation broadens the duration of single exocytotic events. Expression of the orthologous mutation (D214N) in the Caenorhabditis elegans UNC-18 null background generated transgenic rescues with phenotypically similar locomotion to worms rescued with the wildtype protein. Strikingly, D214N worms were strongly resistant to both stimulatory and sedative effects of acute ethanol. Analysis of an alternative Munc18–1 mutation (I133V) supported the link between reduced SNARE complex binding and ethanol resistance.

We conclude that ethanol acts, at least partially, at the level of vesicle fusion and that its acute effects are ameliorated by point mutations in UNC-18.

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