Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors

Cell. 2009 May 29;137(5):949-60. doi: 10.1016/j.cell.2009.03.020. Epub 2009 May 21.

Abstract

The consequences of alcohol use disorders (AUDs) are devastating to individuals and society, yet few treatments are currently available. To identify genes regulating the behavioral effects of ethanol, we conducted a genetic screen in Drosophila and identified a mutant, happyhour (hppy), due to its increased resistance to the sedative effects of ethanol. Hppy protein shows strong homology to mammalian Ste20 family kinases of the GCK-1 subfamily. Genetic and biochemical experiments revealed that the epidermal growth factor (EGF)-signaling pathway regulates ethanol sensitivity in Drosophila and that Hppy functions as an inhibitor of the pathway. Acute pharmacological inhibition of the EGF receptor (EGFR) in adult animals altered acute ethanol sensitivity in both flies and mice and reduced ethanol consumption in a preclinical rat model of alcoholism. Inhibitors of the EGFR or components of its signaling pathway are thus potential pharmacotherapies for AUDs.

Publication types

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

MeSH terms

  • Alcohol-Induced Disorders / metabolism*
  • Animals
  • Crosses, Genetic
  • Disease Models, Animal*
  • Dopamine / metabolism
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / chemistry
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • ErbB Receptors / metabolism*
  • Ethanol / metabolism*
  • Female
  • Insulin / metabolism
  • Male
  • Mice
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*

Substances

  • Drosophila Proteins
  • Insulin
  • Ethanol
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • hppy protein, Drosophila
  • Dopamine