Kv2.1 Channel Modulation of Ethanol Withdrawal

描述(申请人提供)：电压依赖性钾通道(Kv)动态调节固有的神经元兴奋性。越来越多的证据表明，Kv2.1通道在体内平衡可塑性以及在调节兴奋性和重复放电过程中钙内流方面发挥着特别显著的作用。因此，这项提议的广泛、长期的目标是表征Kv2.1通道在控制与酒精戒断相关的过度兴奋性方面所起的作用。这些研究将采用具有良好特征的酒精戒断的器官型海马片培养模型和包括共聚焦成像、免疫组织化学、电生理学和生化分析在内的技术。其具体目的是：[1]确定阻断或击倒Kv2.1通道是否调制乙醇戒断过程中动作电位的放电频率，以及[2]检验Kv2.1对兴奋性的调制的变化将反映为通道的膜定位和磷酸化的变化的假设。这些研究的发现可能为可能的药物设计提供一个新的治疗靶点，以治疗酒精戒断的严重程度，并有可能复发。

DESCRIPTION (provided by applicant): Voltage-dependent potassium channels (Kv) dynamically regulate intrinsic neuronal excitability. Increasing evidence suggests that Kv2.1 channels play an especially prominent role in homeostatic plasticity and in modulating excitability and calcium entry during repetitive firing. Thus, the broad, long-term objective of this proposal is to characterize the role that Kv2.1 channels play in controlling hyperexcitability associated with alcohol withdrawal. These studies will employ a well-characterized organotypic hippocampal slice culture model of alcohol withdrawal and techniques including confocal imaging, immunohistochemistry, electrophysiology, and biochemical assays. The specific aims are to: [1] determine if blocking or knocking-down Kv2.1 channels modulate the frequency of action potential firing during ethanol withdrawal, and [2] to test the hypothesis that changes in Kv2.1 modulation of excitability will be reflected as changes in membrane localization and phosphorylation of the channel. Findings from these studies may implicate a novel therapeutic target for possible drug design to treat the severity of alcohol withdrawal and, potentially, relapse.