Ethanol is a widely consumed intoxicant with effects ranging from increased activity and loss of inhibition at lower doses to decreased activity and sedation at higher concentrations. The molecular mechanisms by which ethanol triggers these changes in behavior and the mechanisms underlying ethanol addiction are areas of active investigation. Corl et al. screened fruit flies, which show similar behavioral responses as people do to ethanol intoxication, for resistance to the sedative effects of ethanol and identified a gene that they named happyhour (hppy), which encodes a Ste20 family kinase homolog. Two different mutants exhibited reduced transcript abundance, and flies carrying these mutants showed increased resistance to ethanol-induced sedation, which was rescued by neuronal-specific expression of hppy. Because many Ste20 family kinases function in mitogen-activated protein kinase (MAPK) cascades, the authors investigated whether a MAPK pathway was involved in mediating the sensitivity to the sedating effects of ethanol. Neither changing the activity of the c-Jun N-terminal kinase (JNK) nor changing that of the p38 MAPK kinase pathway affected the flies' sensitivity to ethanol, but manipulations that enhanced signaling through the epidermal growth factor receptor (EGFR) pathway, which signals through the extracellular signal–regulated kinase (ERK) pathway, increased the resistance to ethanol-induced sedation. Conversely, conditions that inhibited EGFR signaling, genetic or pharmacological, resulted in flies that were more sensitive to the sedating effects of ethanol. Consistent with hppy functioning as a negative regulator of EGFR signaling, hppy exhibited genetic interactions with the EGFR pathway when overexpressed in the fly eye—suppressing the rough eye phenotype associated with enhanced EGFR signaling and enhancing the phenotypes associated with decreased EGFR signaling. To address whether similar mechanisms functioned in mammals, mice and rats were treated with an EGFR inhibitor and then exposed to ethanol. Mice in which EGFR signaling was inhibited recovered more slowly from a sedating dose of ethanol, and the consumption of ethanol was decreased in rats in which EGFR signaling was inhibited. Thus, EGFR signaling appears to play a role in ethanol preference and behavioral changes associated with ethanol consumption. The molecular mechanism by which ethanol influences hppy and EGFR signaling remains unknown, as does the mechanism by which hppy inhibits EGFR signaling (see Palfreyman for commentary).
A. B. Corl, K. H. Berger, G. Ophir-Shohat, J. Gesch, J. A. Simms, S. E. Bartlett, U. Heberlein, Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors. Cell 137, 949–960 (2009). [PubMed]
M. T. Palfreyman, With Happyhour, everyone's under the table. Cell 137, 802–804 (2009). [Online Journal]