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

被引：84

作者：

Corl, Ammon B. ^{[1
]}

Berger, Karen H. ^{[3
]}

Ophir-Shohat, Galit ^{[2
]}

Gesch, Julie ^{[3
]}

Simms, Jeffrey A. ^{[3
]}

Bartlett, Selena E. ^{[3
]}

Heberlein, Ulrike ^{[1
,2
,3
]}

机构：

[1] Univ Calif San Francisco, Program Neurosci, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[3] Ernest Gallo Res Ctr, Emeryville, CA 94608 USA

来源：

CELL | 2009年 / 137卷 / 05期

关键词：

TARGETED GENE-EXPRESSION; GROWTH-FACTOR RECEPTOR; GERMINAL CENTER KINASE; N-TERMINAL KINASE; PROTEIN-KINASE; DROSOPHILA-MELANOGASTER; ALCOHOL DEPENDENCE; BINDING PROTEIN; LOW-LEVEL; PATHWAY;

D O I：

10.1016/j.cell.2009.03.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 amutant, happyhour (hppy), dueto 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.

引用

页码：949 / 960

页数：12

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