論文 - 詳細
| RRC ID | 36172 |
|---|---|
| 著者 | Acevedo SF, Peru y Colón de Portugal RL, Gonzalez DA, Rodan AR, Rothenfluh A. |
| タイトル | S6 Kinase Reflects and Regulates Ethanol-Induced Sedation. |
| ジャーナル | J Neurosci |
| Abstract |
UNLABELLED: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. SIGNIFICANCE STATEMENT: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. |
| 巻・号 | 35(46) |
| ページ | 15396-402 |
| 公開日 | 2015-11-18 |
| DOI | 10.1523/JNEUROSCI.1880-15.2015 |
| PII | 35/46/15396 |
| PMID | 26586826 |
| PMC | PMC4649009 |
| MeSH | ADP-Ribosylation Factor 6 ADP-Ribosylation Factors / genetics ADP-Ribosylation Factors / metabolism Action Potentials / drug effects Action Potentials / genetics Analysis of Variance Animals Animals, Genetically Modified Antigens, CD Cell Line Central Nervous System Depressants / pharmacology* Drosophila Drosophila Proteins / genetics Drosophila Proteins / metabolism Ethanol / pharmacology* Gene Expression Regulation / drug effects* Gene Expression Regulation / genetics* Immunosuppressive Agents / administration & dosage Neurons RNA Interference / physiology Receptor, Insulin / metabolism Ribosomal Protein S6 Kinases, 70-kDa / genetics Ribosomal Protein S6 Kinases, 70-kDa / metabolism* Signal Transduction / physiology Sirolimus / administration & dosage Transcription Factors / genetics Transcription Factors / metabolism |
| IF | 5.674 |
| 引用数 | 6 |
| WOS 分野 | NEUROSCIENCES |
| リソース情報 | |
| ショウジョウバエ | DGRC#104910 |