乙醇的不同行为反应由交替的RhoGAP18B同工型调节。

Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms.

作者信息

Rothenfluh Adrian, Threlkeld Robert J, Bainton Roland J, Tsai Linus T-Y, Lasek Amy W, Heberlein Ulrike

机构信息

Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.

出版信息

Cell. 2006 Oct 6;127(1):199-211. doi: 10.1016/j.cell.2006.09.010.

DOI:10.1016/j.cell.2006.09.010

PMID:17018286

Abstract

In most organisms, low ethanol doses induce increased activity, while high doses are sedating. To investigate the underlying mechanisms, we isolated Drosophila mutants with altered ethanol responsiveness. Mutations in white rabbit (whir), disrupting RhoGAP18B, are strongly resistant to the sedating effects of ethanol. This resistance can be suppressed by reducing the levels of Rho1 or Rac, implicating these GTPases in the behavioral response to ethanol. Indeed, expression of constitutively active forms of Rho1 or Rac1 in adult flies results in ethanol resistance similar to that observed in whir mutants. The whir locus produces several transcripts, RA-RD, which are predicted to encode three distinct RhoGAPs that share only the GAP domain. The RC transcript mediates the sedating effects of ethanol, while the RA transcript regulates its stimulant effects. Thus, distinct RhoGAPs, encoded by the same gene, regulate different manifestations of acute ethanol intoxication.

摘要

在大多数生物体中，低剂量乙醇会诱导活性增加，而高剂量则具有镇静作用。为了研究其潜在机制，我们分离出了乙醇反应性改变的果蝇突变体。白兔（whir）基因发生突变，破坏了RhoGAP18B，对乙醇的镇静作用具有很强的抗性。通过降低Rho1或Rac的水平可以抑制这种抗性，这表明这些GTP酶参与了对乙醇的行为反应。事实上，在成年果蝇中表达组成型活性形式的Rho1或Rac1会导致产生类似于在whir突变体中观察到的乙醇抗性。whir基因座产生几种转录本，RA - RD，预计它们编码三种仅共享GAP结构域的不同RhoGAP。RC转录本介导乙醇的镇静作用，而RA转录本调节其刺激作用。因此，由同一基因编码的不同RhoGAP调节急性乙醇中毒的不同表现。