Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms.
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.
Rothenfluh
Adrian
A
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. adrian.rothenfluh@ucsf.edu
Threlkeld
Robert J
RJ
Bainton
Roland J
RJ
Tsai
Linus T-Y
LT
Lasek
Amy W
AW
Heberlein
Ulrike
U
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D019076:Transgenes; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D002492:Central Nervous System Depressants; D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; C000607926:RhoGAP18B protein, Drosophila; C085379:rho GTPase-activating protein; D000431:Ethanol; D020741:rho GTP-Binding Proteins