Alcohol and the actin cytoskeleton
It has been known for a while that when cultured cells are exposed to ethanol in the medium, they dramatically rearrange the cytoskeleton. The functional significance of that has not been established.
Rho-type GTPases are well known to regulate actin cytoskeleton dynamics. We have isolated a mutant fly strain affecting a regulator of Rho-type GTPases, RhoGAP18B. These mutant flies are resistant to the sedative effects of ethanol.
what we do
page 3
Cultured astrocytes stained for filamentous actin, exposed to various ethanol concentrations. Ethanol leads to formation of actin rings around the periphery.
From Thoma et al. 2003.
Drosophila cells stained for filamentous actin (red). Expression of the RhoGAP18B protein (green) induces actin rearrangements and a spiked appearance of the cells, showing that RhoGAP18B regulates the cytoskeleton.
Current questions
The RhoGAP18B gene produces different RNA transcripts, RA and RC. Interestingly, the lack of RA results in behavioral changes in ethanol-induced hyperactivity, while the loss of RC leads to resistance to alcohol-induced sedation. Thus two isoforms of the same gene affect two successive drug-induced behaviors.
Do the two isoforms participate in the same molecular pathways to affect behavior? Are they required in the same type of neurons for normal behavior? And how exactly do the two isoforms differ? These are some of the questions we are currently pursuing.