Alcohol Actin Dynamics and Ethanol Sensitivity

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

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--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]