We are interested the molecular bases of ethanol response in C. elegans. Natural variation in the acute ethanol response in humans is strongly correlated with the propensity to abuse alcohol such that people with relatively higher innate tolerance are more likely to become alcoholic (Schuckit, 2002). Worms get drunk at similar concentrations of ethanol to those that intoxicate humans, suggesting that there is a conserved mechanism for the effects of ethanol on the nervous system, and that worms can be a good model for studying ethanol responses. Worms become progressively more uncoordinated, slow and Egl as the ethanol dose increases (Davies et al., 2003). In response to exposure to a constant ethanol concentration, worms undergo an acute adaptation (acute tolerance) to the presence of ethanol that does not reflect a decrease in tissue ethanol concentration. There is substantial natural variation in the rate of development of acute tolerance between the wild strains N2 and CB4856. This difference between the behavior of the wild strains is due to the previously described allelic variation at the npr-1 locus (de Bono and Bargmann, 1998; Davies et al., 2004). Genetic analysis indicates that NPR-1 activity antagonizes the development of acute tolerance. To better understand the molecular mechanisms of this development of acute tolerance, we have performed a screen for suppressors of the npr-1(ky13) rapid development of acute tolerance phenotype. To date, we have screened approximately 4000 haploid genomes and have recovered 10 suppressors from at least 6 complementation groups. Most of our mutations do not suppress npr-1-mediated clumping, indicating that they identify components that are specific to the acute ethanol tolerance pathway, rather than general suppressors of npr-1. None of the mutations has an obvious phenotype in the absence of ethanol. We have mapped and cloned the first of these suppressors, eg613, which is a null allele of the gene F49E10.5. Analysis of a transcriptional reporter construct reveals that F49E10.5 is expressed in a small subset of neurons. We are pursuing identification of these neurons and exploring the molecular mechanisms by which this molecule affects development of acute ethanol tolerance.

Affiliation:
- Gallo Center, University of California, San Francisco, Emeryville, CA.