S6 Kinase Reflects and Regulates Ethanol-Induced Sedation
S6 Kinase Reflects and Regulates Ethanol-Induced Sedation
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DOI：
10.1523/jneurosci.1880-15.2015
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发表时间：
2015-11-18
影响因子：
5.3
通讯作者：
Rothenfluh, Adrian
中科院分区：
文献类型：
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作者：
Acevedo, Summer F.;de Portugal, Raniero L. Peru y Colon;Rothenfluh, Adrian
酒精使用障碍（AUDs）给人们带来了巨大的个人和社会成本。有aud风险的个体对酒精的奖励作用敏感和/或对其厌恶和镇静作用有抵抗力。人们对这些特征的分子基础知之甚少。在这里，我们发现p70 S6激酶（S6k）作用于胰岛素受体（InR）和小GTPase Arf6的下游，是乙醇诱导果蝇镇静的关键介质。成年神经系统中的S6k信号决定了果蝇对镇静的敏感性。此外，通过磷酸化水平（P-S6k）测量的S6k活性是镇静和整体神经元活动的分子标记：当神经元沉默以及急性乙醇镇静后，P-S6k水平降低。相反，P-S6k水平在镇静恢复后反弹，并在神经元活动增强时增加。神经活动的减少增加了对乙醇诱导镇静的敏感性，而神经元的激活则降低了对乙醇的敏感性。这些数据表明，乙醇对成人神经元活动具有急性沉默作用，其抑制InR/Arf6/S6k信号并导致行为镇静。此外，我们发现InR/Arf6/S6k信号的活性决定了果蝇对乙醇诱导镇静的行为敏感性，强调了这一途径在乙醇急性反应中的作用。
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.