Chronic Ethanol and SK2 Potassium Channels

慢性乙醇和 SK2 钾通道

• 批准号: 8149986
• 负责人: PATRICK J. MULHOLLAND
• 金额: $ 18.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149986
• 关键词: Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Award; Calcium; Chronic; Consumption; Cyclic AMP-Dependent Protein Kinases; Dendritic Spines; Development; Ethanol; Feedback; Glutamates; Hippocampus (Brain); Incidence; Individual; Mediating; N-Methyl-D-Aspartate Receptors; Potassium Channel; Relapse; SK potassium channel; Severities; Signal Transduction; Suggestion; Surface; Synapses; Synaptic plasticity; Testing; Withdrawal; alcohol exposure; craving; drinking behavior; insight; neurotoxicity; new therapeutic target; response

Recent evidence suggests that ethanol-associated homeostatic plasticity involves compensatory increases in synaptic NMDA receptors that contributes to aberrant hyperexcitability upon cessation of consumption and may underlie craving that leads to the high incidence of relapse in alcohol dependent individuals. Small-conductance calcium-activated potassium (SK) channels regulate NMDA receptor-dependent calcium influx and are critical modulators of hippocampal-dependent synaptic plasticity. This is consistent with the suggestion that SK2 channels and NMDA receptors form a regulatory calcium-mediated feedback loop within individual dendritic spines. Preliminary evidence demonstrates a reduction in surface SK2 channels following chronic ethanol treatment that leads to a disruption of the SK channel-NMDA receptor feedback loop. Moreover, we have demonstrated that modulation of SK channels can influence voluntary drinking behavior. Thus, the overarching hypothesis is that SK2 channels contribute to alcohol-associated plasticity of glutamatergic synapses and that positive modulation of SK channels reduces the severity of withdrawal-related hyperexcitability and decreases alcohol intake. These studies will test the hypotheses that: 1) chronic ethanol exposure produces a homeostatic reduction in SK2 channel expression through PKA signaling, 2) modulation of the SK channel-NMDA receptor feedback loop can reduce ethanol withdrawal , hyperexcitability and neurotoxicity, and 3) modulation of the synaptic feedback loop will reduce voluntary alcohol consumption. Decreases in SK2 channels and increases in NMDA receptors may represent a common homeostatic adaptive response to prolonged reductions in NMDA receptor activity during ethanol exposure. Furthermore, this functional uncoupling of the SK2 channel-NMDA receptor calcium-mediated feedback loop may contribute to tolerance development and to withdrawal hyperexcitability.

最近的证据表明，与乙醇相关的稳态可塑性涉及补偿性增加 在突触NMDA受体中，导致停止消费和 可能是渴望导致酒精依赖人复发的高发生率的基础。小导体 钙激活的钾（SK）通道调节NMDA受体依赖性钙流入 并且是海马依赖性突触可塑性的关键调节因子。这与 建议SK2通道和NMDA受体形成一个调节性钙介导的反馈回路 单个树突状刺。初步证据表明表面SK2通道的减少 经过慢性乙醇处理，导致SK通道NMDA受体反馈的破坏 环形。此外，我们已经证明了SK频道的调节会影响自愿饮酒 行为。因此，总体假设是SK2通道有助于酒精相关的可塑性 谷氨酸能突触和SK通道的正调节降低了与戒断相关的严重程度 过度兴奋并减少酒精摄入量。这些研究将检验：1）的假设 慢性乙醇暴露可通过PKA降低SK2通道表达的稳态 信号传导，2）SK通道NMDA受体反馈回路的调节可以减少乙醇的提取， 过度兴奋性和神经毒性，以及3）突触反馈回路的调节将减少自愿性 饮酒。 SK2通道的减少和NMDA受体的增加可能代表 对乙醇期间NMDA受体活性的长时间降低的常见稳态自适应反应 接触。此外，SK2通道NMDA受体钙介导的这种功能解偶联 反馈循环可能有助于耐受性发展和戒断过度兴奋。