Happyhour, a Ste20 Family Kinase, Implicates EGFR Signaling in Ethanol-Induced Behaviors

Ammon B. Corl, Karen H. Berger, Galit Ophir-Shohat, Julie Gesch, Jeffrey A. Simms, Selena E. Bartlett, Ulrike Heberlein

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish
Pages (from-to)949-960
Number of pages12
JournalCell
Volume137
Issue number5
DOIs
StatePublished - 29 May 2009
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Aylin Rodan for initiating this project, Linus Tsai and Ian King for outcrossing many of the lines used in this study, Amy Lasek for designing the primer/probe sets used for hppy QPCR, Melissa Sniffen for assistance with Drosophila CNS dissections, and all other members of the Heberlein lab for thoughtful discussions regarding this project. We thank Kevin Moses, Marek Mlodzik, Tim Tully, Mariann Bienz, Celeste Berg, Kunihiro Matsumoto, Barry Dickson, and the Bloomington Stock Center for providing fly lines. Scanning electron microscopy was performed at the Cornell Integrated Microscopy Center at Cornell University in Ithaca, NY. We gratefully acknowledge the gift of Tarceva from OSI Pharmaceuticals. We also thank Joan Holgate and Carsten Nielsen, in the preclinical development group, for assistance with the rodent experiments. This research was supported by grants from the NIH/NIAAA (U.H.), the Department of Defense (U.H. and S.E.B.), the State of California for Medical Research through UCSF (U.H. and S.E.B.), and the UCSF Neuroscience Training Grant and the ARCS Foundation (A.B.C.).

Keywords

  • HUMDISEASE
  • MOLNEURO
  • SIGNALING

Fingerprint

Dive into the research topics of 'Happyhour, a Ste20 Family Kinase, Implicates EGFR Signaling in Ethanol-Induced Behaviors'. Together they form a unique fingerprint.

Cite this