Discovery and mechanism of BK channel gating modulators

BK通道门控调制器的发现及其机制

• 批准号: 10180981
• 负责人: Brad S. Rothberg
• 金额: $ 31.7万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10180981
• 关键词: Address; Animal Model; Asthma; Biological Assay; Bladder Dysfunction; Calcium-Activated Potassium Channel; Cardiovascular system; Cell Line; Cell Proliferation; Cell membrane; Cells; Collection; Coupled; Development; Disease; Drug Binding Site; Electrophysiology (science); Epilepsy; Epithelial Cells; Erectile dysfunction; Fluorescence; Functional disorder; Gene Targeting; Generalized Epilepsy; Glaucoma; Goals; Human; Hypertension; Kinetics; Lead; Learning; Link; Location; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Medical; Medicine; Membrane Potentials; Molecular; Muscle Cells; Mutagenesis; Mutation; Nerve; Neurons; Paroxysmal Dyskinesias; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Physiological; Physiological Processes; Play; Prostate; Reader; Reagent; Regulation; Research; Rest; Role; Scheme; Secretory Cell; Smooth Muscle; Structure; Testing; Thallium; Tissues; Treatment Protocols; Validation; autism spectrum disorder; base; computer studies; drug action; drug candidate; drug mechanism; experimental study; high throughput screening; human disease; in vivo; inhibitor/antagonist; insight; large-conductance calcium-activated potassium channels; molecular dynamics; nervous system disorder; neuronal excitability; novel; overexpression; patch clamp; prostate cancer cell; screening; sensor; small molecule; small molecule libraries; stable cell line; tool; voltage

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.

项目摘要 大电导钙激活钾通道（SLO-1或BK通道）在钙离子通道的形成中起着关键的生理作用。 在控制神经和平滑肌的活动以及设置静息膜中的作用 在上皮细胞中的潜力。BK通道孔形成（α）或调节（β）亚基缺失 在基因靶向动物模型中，可能导致包括动脉高血压、膀胱和 勃起功能障碍和神经系统疾病，包括癫痫;人BK通道突变 亚基与全身性癫痫伴阵发性运动障碍（GEPD）、哮喘和自闭症有关 在前列腺癌和其他癌症中，Bk通道被上调。选择性BK 因此，通道激活剂以及抑制剂可以成为治疗方案的组成部分， 心血管/神经系统疾病以及脑癌和前列腺癌。利用BK通道作为 作为一个潜在的医学靶点，扩大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展 了解BK通道门控机制，并最终找到新的疾病治疗方法。下 这个建议，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，其目的在于发现用于BK通道的新型门控调节剂，其包括 组织特异性亚基组合，和2）系统的计算和电生理 实验以确定这些药物是否通过相互作用调节BK通道功能 与Ca 2+传感器、电压传感器或通道的孔域。我们的研究计划将 产生新的药理学研究工具来调节BK通道，这将与 建立定量电生理分析的优势，以获得基本的见解 BK通道门控机制，可能会进一步导致新的治疗疾病。