Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors.
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.
Corl
Ammon B
AB
Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94143-2822, USA.
Berger
Karen H
KH
Ophir-Shohat
Galit
G
Gesch
Julie
J
Simms
Jeffrey A
JA
Bartlett
Selena E
SE
Heberlein
Ulrike
U
D020751:Alcohol-Induced Disorders / Q000378:metabolism*; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D029721:Drosophila Proteins; D007328:Insulin; D000431:Ethanol; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C541347:hppy protein, Drosophila; D004298:Dopamine