Corl Ammon B, Berger Karen H, Ophir-Shohat Galit, Gesch Julie, Simms Jeffrey A, Bartlett Selena E, Heberlein Ulrike
Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94143-2822, USA.
Cell. 2009 May 29;137(5):949-60. doi: 10.1016/j.cell.2009.03.020. Epub 2009 May 21.
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.
酒精使用障碍（AUDs）的后果对个人和社会都具有毁灭性，但目前可用的治疗方法很少。为了确定调节乙醇行为效应的基因，我们在果蝇中进行了基因筛选，并鉴定出一个突变体——快乐时光（hppy），因为它对乙醇的镇静作用具有增强的抗性。Hppy蛋白与哺乳动物GCK-1亚家族的Ste20家族激酶具有很强的同源性。遗传和生化实验表明，表皮生长因子（EGF）信号通路调节果蝇对乙醇的敏感性，并且Hppy作为该通路的抑制剂发挥作用。成年动物中表皮生长因子受体（EGFR）的急性药理学抑制改变了果蝇和小鼠的急性乙醇敏感性，并减少了酒精中毒临床前大鼠模型中的乙醇消耗。因此，EGFR抑制剂或其信号通路的组成部分是治疗AUDs的潜在药物疗法。
