Abstract
The molecular mechanisms underlying sensitivity to alcohol are incompletely understood. Recent research has highlighted the involvement of two presynaptic proteins, Munc18 and Rab3. We have previously characterised biochemically a number of specific Munc18 point mutations including an E466K mutation that augments a direct Rab3 interaction. Here the phenotypes of this and other Munc18 mutations were assessed in alcohol sensitivity and exocytosis using Caenorhabditis elegans. We found that expressing the orthologous E466K mutation (unc-18 E465K) enhanced alcohol sensitivity. This enhancement in sensitivity was surprisingly independent of rab-3. In contrast unc-18 R39C, which decreases syntaxin binding, enhanced sensitivity to alcohol in a manner requiring rab-3. Finally, overexpression of R39C could suppress partially the reduction in neurotransmitter release in rab-3 mutant worms, whereas wild-type or E465K mutants showed no rescue. These data indicate that the epistatic interactions between unc-18 and rab-3 in modulating sensitivity to alcohol are distinct from interactions affecting neurotransmitter release.
Highlights
Drug addiction is one of the leading causes of preventable death, generating a considerable financial burden to society
To assess whether these other Munc18 interactions could affect alcohol sensitivity we generated transgenic worms expressing the orthologous mutations of unc-18 in a null background (Figure 1A) and assessed their sensitivity to alcohol in comparison with transgenic worms expressing wildtype unc-18
The unc-18 R39C, P240S and E465K expressing mutants exhibited qualitatively normal locomotion in comparison to unc-18 wild-type (Table 1) the R39C mutants had a significant reduction in thrashing of 23% in comparison to wild-type (Kruskal-Wallis one-way analysis of variance on ranks with post-hoc comparison; P
Summary
Drug addiction is one of the leading causes of preventable death, generating a considerable financial burden to society. Alcohol use and abuse can lead to increased incidence of liver disease, cardiovascular disease, cancer and other debilitating illnesses [1]. The environment can influence addiction, current estimates of genetic heritability range between 40-80% [2]. One significant contributing component to the genetic determination of addiction is the individual’s initial level of response as highlighted by a consistent association of alcohol addiction with polymorphisms in genes involved in alcohol metabolism [3,4]. Despite a ubiquitous prevalence in modern society, the precise physiological mechanisms of intoxication and addiction remain poorly understood. A complete understanding of the contributing factors that underlie alcohol sensitivity is of potential therapeutic importance
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