Kv2.1 Channel Modulation of Ethanol Withdrawal

描述（由申请人提供）：电压依赖性钾通道（Kv）动态调节内在神经元兴奋性。越来越多的证据表明，Kv2.1通道发挥特别突出的作用，在稳态可塑性和调节兴奋性和钙离子内流在重复放电。因此，该提议的广泛的长期目标是表征Kv2.1通道在控制与酒精戒断相关的过度兴奋中发挥的作用。这些研究将采用一个充分表征的器官型海马切片培养模型的酒精戒断和技术，包括共聚焦成像，免疫组织化学，电生理学和生化测定。具体目标是：[1]确定阻断或敲低Kv2.1通道是否调节乙醇戒断期间动作电位放电的频率，[2]检验兴奋性Kv2.1调节的变化将反映为通道膜定位和磷酸化的变化的假设。这些研究的结果可能涉及一种新的治疗靶点，用于可能的药物设计，以治疗酒精戒断的严重程度和潜在的复发。

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.