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Discovery and mechanism of BK channel gating modulators

BK通道门控调制器的发现及其机制

基本信息

批准号：
10388686
负责人：
Brad S. Rothberg
金额：
$ 8.42万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY Large conductance calcium-activated K channels (SLO-1 or BK channels) play a key physiological role in limiting smooth muscle contractility and neuronal excitability. 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. BK channel activators could thus become components of treatment regimens for cardiovascular and/or neurological disease. To exploit BK channels as a potential medical target, it will be important to expand our molecular arsenal of BK channel activators 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 cardiovascular and neurological 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 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. This equipment supplement will be used for purchase of an isothermal titration calorimeter (ITC) that is capable of directly determining thermodynamic binding constants in drug-receptor interactions. This tool will greatly enhance our research to yield fundamental insights toward BK channel gating mechanisms that may further lead to new treatments for disease.

项目总结大电导钙激活K通道(SLO-1或BK通道)起关键作用限制平滑肌收缩和神经元兴奋性的生理作用。删除BK 基因靶向动物模型中的通道孔道形成(α)或调节(β)亚单位可以导致动脉高血压、膀胱和勃起功能障碍等疾病，以及包括癫痫在内的神经疾病；人类BK通道亚单位的突变与全身性癫痫伴阵发性运动障碍(GEPD)、哮喘和自闭症精神错乱。因此，BK通道激活剂可能成为治疗方案的组成部分心血管和/或神经疾病。利用BK渠道作为潜在的医疗手段目标，重要的是扩大我们的BK通道激活剂的分子武器库，并学习它们的作用机制。这样做将导致理解BK的整体努力取得进展经络门控机制，并最终找到新的治疗心血管和神经系统疾病。根据这项建议，我们将通过以下组合来实现这些目标 1)基于细胞的荧光筛选，其目的是发现新的门控调节器由组织特异性亚单位组合组成的BK通道，以及2)系统性电生理实验确定这些药物是否调制BK通道通过与钙离子传感器、电压传感器或孔域的相互作用发挥作用频道。这项设备补充将用于购买等温滴定量热计。 (ITC)可直接测定药物受体的热力学结合常数互动。这一工具将极大地加强我们的研究，以产生对BK的基本见解通道门控机制，可能进一步导致新的疾病治疗方法。