Actin Dynamics and Ethanol Sensitivity
Authors: Adler Elizabeth M. 
Published: December 2006

The risk of alcoholism has been associated with resistance to the acute intoxicating effects of alcohol, leading researchers to explore model systems that might give insight into the molecular factors that modulate ethanol sensitivity. Two studies suggest that ability to regulate the actin cytoskeleton could influence sensitivity to alcohol. Rothenfluh
et al
. found that mutations of the
Drosophila
RhoGAP18B
locus, which was predicted to encode three RhoGAP18 proteins that shared only the guanosine triphosphatase (GTPase) activating protein (GAP) domain, led to resistance to ethanol-induced sedation (assessed by the loss-of-righting test and locomotor tracking) that was specifically associated with loss of the
RhoGAP18B-RC
transcript. Experiments with dominant-negative or constitutively active Rho GTPases and loss-of-function alleles suggested that the effects of
RhoGAP18B-RC
on ethanol-induced sedation were mediated though Rho1 or the Rac GTPases (or both) but not through Cdc42. In contrast to
RhoGAP18B-RC
, the
RhoGAP18B-RA
transcript appeared to be involved in mediating ethanol’s stimulant effects.

As Sordella and Van Aelst note, the Rho GTPases have been implicated in regulation of actin dynamics; the second study, by Offenhäuser
et al
., investigated ethanol resistance in mice of Eps8, which is also involved in regulating actin dynamics. Mice lacking Eps8 (
Eps8
-KO mice) showed increased ethanol consumption and were less sensitive to the sedative and motor-incoordinating effects of ethanol but not to its stimulation of locomotor activity. Eps8 was observed in dendritic articulations of cerebellar granule neurons (CGNs); it was present in cerebellar postsynaptic density fractions, and it coimmunoprecipitated with the
N
-methyl-𝒟-aspartate (NMDA)-type glutamate receptor (NMDAR). Electrophysiological recordings from CGNs in cerebellar slices indicated that the NMDA component of the composite excitatory postsynaptic current was increased in
Eps8
-KO compared with that of wild-type mice and was less sensitive to inhibition by 400 mM ethanol. Introduction of Eps8 into
Eps8
-KO neurons reduced NMDAR-mediated currents, as did latrunculin (which disrupts actin filaments). Eps8 was present in F-actin-rich clusters in the neurites of cultured CGNs; glutamate or NMDA treatment led to a decrease in cofilin phosphorylation and a loss of F-actin from these structures, effects that were attenuated in
Eps8
-KO neurons. Ethanol treatment also elicited a loss of F-actin from these structures and in cerebellar slices, effects to which
Eps8
-KO neurons were resistant. Thus, both
Drosophila
and mouse studies suggest that disruption of the mechanisms involved in regulating actin dynamics affects sensitivity to ethanol.

A. Rothenfluh, R. J. Threlkeld, R. J. Bainton, L. T.-Y. Tsai, A. W. Lasek, U. Heberlein, Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms.
Cell
127
, 199-211 (2006).
[PubMed]

N. Offenhäuser, D. Castelletti, L. Mapelli, B. E. Soppo, M. C. Regondi, P. Rossi, E. D'Angelo, C. Frassoni, A. Amadeo, A. Tocchetti, B. Pozzi, A. Disanza, D. Guarnieri, C. Betsholtz, G. Scita, U. Heberlein, P. P. Di Fiore, Increased ethanol resistance and consumption in
Eps8
knockout mice correlates with altered actin dynamics.
Cell
127
, 213-226 (2006).
[PubMed]

R. Sordella, L. Van Aelst, Driving actin dynamics under the influence of alcohol.
Cell
127
, 37-39 (2006).
[PubMed]