Discovery and mechanism of BK channel gating modulators

项目总结 大电导钙激活的钾通道(SLO-1或BK通道)起着关键的生理作用 在控制神经和平滑肌活动以及设置静息膜方面的作用 上皮细胞的潜能。BK通道成孔(α)或调节(β)亚基的缺失 在基因靶向的动物模型中，可能会导致包括动脉高血压、膀胱和 勃起功能障碍和包括癫痫在内的神经疾病；人类BK通道突变 亚基与全身性癫痫伴发作性运动障碍(GEPD)、哮喘和自闭症有关 谱系紊乱，BK通道在前列腺癌和其他癌症中上调。选择性BK 因此，通道激活剂和抑制剂可以成为治疗方案的组成部分 心血管/神经疾病以及脑癌和前列腺癌。要利用BK频道作为 潜在的医学靶点，扩大我们的BK通道激活剂的分子库将是重要的 和抑制剂，并了解它们的作用机制。这样做将导致整体努力的进步。 了解BK通道门控机制，最终找到治疗疾病的新方法。在……下面 在这项提议中，我们将通过结合基于细胞的荧光来实现这些目标 筛选，其目的是发现用于BK信道的新的门控调制器，包括 组织特异性亚基组合，以及2)系统的计算和电生理 确定这些药物是否通过相互作用调节BK通道功能的实验 与钙离子传感器、电压传感器或通道的孔域结合。我们提议的研究将 产生新的药理研究工具来调制BK通道，这将与 在定量电生理分析方面具有公认的优势，以获得基本见解 BK通道门控机制，这可能进一步导致新的疾病治疗方法。

PROJECT SUMMARY Large conductance calcium-activated K channels (SLO-1 or BK channels) play a key physiological role in controlling activity of nerve and smooth muscle, as well as setting the resting membrane potential in epithelial cells. Deletion of BK channel pore-forming (alpha) or modulatory (beta) subunits in gene-targeted animal models can lead to diseases that include arterial hypertension, bladder and erectile dysfunction, and neurological disorders including epilepsy; mutations in human BK channel subunits are linked to generalized epilepsy with paroxysmal dyskinesia (GEPD), asthma, and autism spectrum disorders, and BK channels are upregulated in prostate and other cancers. Selective BK channel activators, as well as inhibitors, could thus become components of treatment regimens for cardiovascular/neurological disease and brain and prostate cancers. To exploit BK channels as a potential medical target, it will be important to expand our molecular arsenal of BK channel activators and inhibitors and learn their mechanisms of action. Doing so will lead to advances in an overall effort to understand BK channel gating mechanisms and ultimately find new treatments for disease. Under this proposal, we will achieve these goals through a combination of 1) cell-based fluorescent screening, which is aimed at discovery of novel gating modulators for BK channels comprised of tissue-specific subunit combinations, and 2) systematic computational and electrophysiological experiments to determine whether these drugs modulate BK channel function through interactions with the Ca2+-sensor, voltage-sensor, or pore domains of the channel. Our proposed research will generate new pharmacological research tools to modulate BK channels, which will be combined with established strengths in quantitative electrophysiological analysis, to gain fundamental insights toward BK channel gating mechanisms that may further lead to new treatments for disease.