An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

PLoS One. 2011;6(7):e22636. doi: 10.1371/journal.pone.0022636. Epub 2011 Jul 22.

Abstract

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.

Publication types

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

MeSH terms

  • Alcohol Drinking / genetics
  • Alcoholics
  • Anaplastic Lymphoma Kinase
  • Animals
  • Behavior, Animal / drug effects*
  • Conscious Sedation
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / genetics
  • Ethanol / pharmacology*
  • Evolution, Molecular*
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Polymorphism, Genetic / genetics
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*

Substances

  • Bx protein, Drosophila
  • Drosophila Proteins
  • Homeodomain Proteins
  • Ethanol
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases