RRC ID 46270
Author Bettinger JC, Leung K, Bolling MH, Goldsmith AD, Davies AG.
Title Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans.
Journal PLoS One
Abstract The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via the lipase LIPS-7, indicating that there is an important role for TAGs in the development of tolerance. Genetic manipulation of lips-7 expression, up or down, produced opposing effects on ethanol sensitivity and on the rate of development of AFT. Further, decreasing cholesterol levels through environmental manipulation mirrored the effects of decreased TAG levels. Finally, we found that genetic alterations in the levels of the TAG lipase LIPS-7 can modify the phenotype of gain-of-function mutations in the ethanol-inducible ion channel SLO-1, the voltage- and calcium-sensitive BK channel. This study demonstrates that the lipid milieu modulates neuronal responses to ethanol that include initial sensitivity and the development of acute tolerance. These results lend new insight into studies of alcohol dependence, and suggest a model in which TAG levels are important for the development of AFT through alterations of the action of ethanol on membrane proteins.
Volume 7(5)
Pages e35192
Published 2012-1-1
DOI 10.1371/journal.pone.0035192
PII PONE-D-12-05143
PMID 22574115
PMC PMC3344825
MeSH Animals Caenorhabditis elegans / drug effects* Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cholesterol / metabolism Down-Regulation / drug effects Ethanol / pharmacology* Lipid Metabolism / drug effects* Mutation Phenotype Triglycerides / metabolism
IF 2.74
Times Cited 25
C.elegans tm420