EFA6/PSD3, Arf6 Modulator, Regulates Ethanol-Induced Behaviors Via the Insulin Receptor Signaling Pathway in Flies and Humans




Gonzalez, Dante Alan

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Despite the tremendous hazard that alcohol (ethanol) poses to society world-wide, our progress on the molecular and physiological understanding of how ethanol use disorders (AUD) develop has been marginal. Our limited progress can be credited to the wide range of effects that ethanol has on the body, absence of a known high affinity receptor to ethanol, and large phenotypic heterogeneities, which have been shown in genome wide association studies (GWAS). In the United States alone, AUD are highly prevalent with approximately ~18 million adults aged 18 and up and ~1 million adolescents ages 12-17 diagnosed with AUD in 2012. AUD have profound clinical significance and show to be strongly heritability, up to ~60% based on family, adoption, and twin studies. My focus in the laboratory was to understand the mechanisms by which ethanol-induced behaviors are regulated. Some of the most recognizable effects of ethanol include: sedation, tolerance, and voluntary alcohol preference (the most salient aspect of alcohol dependence). To study these behaviors, I used Drosophila melanogaster as a model organism. Drosophila displays behavioral ethanol-induced behaviors just like humans, and it has high genetic conservation with humans. Furthermore, from a pragmatic aspect, flies are easy to maintain, yield high numbers of progeny, and can be easily Here I provide evidence that in Drosophila, a guanine nucleotide exchange factor (GEF) of Arf6, EFA6, molecularly regulates the activity of Arf6 as well as the behavioral output of Arf6. I show that EFA6 mutant flies are 1) hypersensitive to the effects of ethanol 2) they do not develop tolerance following a pre-exposure, and 3) altered in their preference for ethanol. Arf6 mutant flies also show similar alcohol-induced behaviors as EFA6 mutants, which can be rescued to wild type levels when Arf6 is re-expressed in Arf6 expressing cells. These results are also translatable to human behavior. In collaboration with Dr. Gunter Schummann from King's College London, we show that 1 out of the 4 human homologues (PSD1-4) of EFA6, PSD3 (pleckstrin Sec7 domain 3) is associated with frequency of drinking in 14 year old adolescents from the IMAGEN consortium. . Furthermore, I show that p70 S6 kinase (S6k), acting downstream of the insulin receptor tyrosine kinase (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular correlate of sedation and overall neuronal activity; P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation, and they are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, while neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, I show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol. Taken together, my data significantly expand our knowledge of ethanol-induced behaviors; they give us great insights into AUD development, and may serve in the development of better treatments or therapies for alcoholism.

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