title: S6 Kinase Reflects and Regulates Ethanol-Induced Sedation.
abstract: Alcohol use disorders (AUDs) affect people at great individual and societal cost. Individuals at risk for AUDs are sensitive to alcohol's rewarding effects and/or resistant to its aversive and sedating effects. The molecular basis for these traits is poorly understood. Here, we show that p70 S6 kinase (S6k), acting downstream of the insulin receptor (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. Furthermore, S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular marker for 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 are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, whereas 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, we show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol.
  
  
  CONCLUSIONS
  Genetic factors play a major role in the development of addiction. Identifying these genes and understanding their molecular mechanisms is a necessary first step in the development of targeted therapeutic intervention. Here, we show that signaling from the insulin receptor in Drosophila neurons determines flies' sensitivity to ethanol-induced sedation. We show that this signaling cascade includes the small GTPase Arf6 and S6 kinase (S6k). In addition, activity of S6k is regulated by acute ethanol exposure and by neuronal activity. S6k activity is therefore both an acute target of ethanol exposure and a regulator of ethanol's effects on behavior.
authors.affiliation: Department of Psychiatry.
authors.forename: Summer F
authors.initials: SF
authors.lastname: Acevedo
authors.affiliation: Department of Psychiatry, Program in Neuroscience, and.
authors.forename: Raniero L
authors.initials: RL
authors.lastname: Peru y Colón de Portugal
authors.affiliation: Department of Psychiatry, Program in Neuroscience, and.
authors.forename: Dante A
authors.initials: DA
authors.lastname: Gonzalez
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Aylin R
authors.identifier: http://orcid.org/0000-0001-9202-2378
authors.initials: AR
authors.lastname: Rodan
authors.affiliation: Department of Psychiatry, Program in Neuroscience, and Adrian.Rothenfluh@UTSouthwestern.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Rothenfluh
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D009474:Neurons; D034622:RNA Interference / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D015703:Antigens, CD; D002492:Central Nervous System Depressants; D029721:Drosophila Proteins; C557617:GAL4 protein, Drosophila; D007166:Immunosuppressive Agents; D014157:Transcription Factors; D000431:Ethanol; C435941:INSR protein, human; D011972:Receptor, Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020123:Sirolimus
keywords: Arf6; Drosophila; S6 kinase; addiction; ethanol; insulin receptro