TY - JOUR
T1 - Distinct Behavioral Responses to Ethanol Are Regulated by Alternate RhoGAP18B Isoforms
AU - Rothenfluh, Adrian
AU - Threlkeld, Robert J.
AU - Bainton, Roland J.
AU - Tsai, Linus T Y
AU - Lasek, Amy W.
AU - Heberlein, Ulrike
N1 - Funding Information:
We thank members of the Heberlein laboratory for discussions and critical reading of the manuscript, especially Aylin Rodan, Doug Guarnieri, Rachael French, and Mark Eddison. We also thank Kevin Lease and Jay Hirsh for communicating results prior to publication; the Bloomington Drosophila Stock Center, Liqun Luo, and the Japanese NP consortium for fly strains; and Alois Hofbauer for nc82 antibody. Susan Parkhurst and Jörg Grosshans kindly provided expression vectors. The manuscript benefited greatly from comments by Justin Blau and Larry Tecott. This research was supported by the Swiss Society for Biomedical Stipends (A.R.) and NIH grants AA10035, AA13105, and DA14809 (U.H.).
PY - 2006/10/6
Y1 - 2006/10/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2006.09.010
DO - 10.1016/j.cell.2006.09.010
M3 - Article
C2 - 17018286
AN - SCOPUS:33749058095
SN - 0092-8674
VL - 127
SP - 199
EP - 211
JO - Cell
JF - Cell
IS - 1
ER -