Rsu1 regulates ethanol consumption in Drosophila and humans

Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4085-93. doi: 10.1073/pnas.1417222112. Epub 2015 Jul 13.


Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

Keywords: actin; addiction; alcohol; genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adolescent
  • Adult
  • Alcohol Drinking / genetics*
  • Animals
  • Brain / metabolism
  • Cell Adhesion Molecules / metabolism
  • Child
  • Cohort Studies
  • Cytoskeleton / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • Ethanol / chemistry
  • Female
  • GTP Phosphohydrolases / metabolism
  • Genes, Dominant
  • Humans
  • Integrins / metabolism
  • Male
  • Mutation
  • Neurons / metabolism
  • Polymorphism, Genetic
  • Surveys and Questionnaires
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • Actins
  • Cell Adhesion Molecules
  • Drosophila Proteins
  • Integrins
  • Transcription Factors
  • ics protein, Drosophila
  • RSU1 protein, human
  • Ethanol
  • GTP Phosphohydrolases