Modulation of KCNQ1 channel activity

KCNQ1 通道活性的调节

• 批准号: 8657285
• 负责人: ROBERT S KASS
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657285
• 关键词: Action Potentials; Affect; Animals; Arrhythmia; Atrial Fibrillation; Basic Science; Cardiac; Clinical; Defect; Disease; Electrocardiogram; Epithelium; Future; Genetic Polymorphism; Heart; Heart Atrium; Inherited; KCNQ1 protein; Long QT Syndrome; Measures; Membrane; Molecular; Movement; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Play; Potassium Channel; Predisposition; Role; Syndrome; Testing; Therapeutic; Time; Tissues; cell type; deafness; disease-causing mutation; functional restoration; heart rhythm; inhibitor/antagonist; kidney cell; kidney epithelial cell; mutant; response; sensor; small molecule; spine bone structure; voltage

DESCRIPTION (provided by applicant): The KCNQ1 voltage gated K+ channel is expressed in many different tissues and plays widely different roles in these different tissues. Mutations and polymorphisms in KCNQ1 have been implicated in multiple diseases, including cardiac arrhythmias, inherited deafness, and susceptibility to type 2 diabetes. In the heart, KCNQ1 is co-expressed with the beta subunit KCNE1 to form the slowly activating, voltage gated IKs channels that contribute critically to the repolarization of the cardiac action potential at the cellular level and the QT interval of the electrocardiogram. In other cell types, such as epithelia and kidney cells, KCNQ1 is co-expressed with the beta subunits KCNE2 or KCNE3 to form a voltage independent K+ channel that is important for K+ and Cl- secretion. The critical role of KCNQ1 has been revealed by inherited mutations which have been associated with such diverse cardiac rhythm disturbances as the Long QT syndrome, the Short QT Syndrome, and atrial fibrillation. In many cases, co-assembly with the KCNE1 ¿ subunit dictates pathological function. How different beta subunits and mutations alter the function of KCNQ1 channels is not completely understood. We will here simultaneously measure the movement of the voltage sensor and the activation gate in KCNQ1 channels. This will allow us to determine whether a specific beta subunit or mutation mainly affects the voltage sensor or the gate. We will also test the effects of different modulators, both activators and inhibitors, of KCNQ1 on the voltage sensor movement and the activation gate, in order to understand how these molecules affect KCNQ1 activity and whether these molecules can restore the function of mutant KCNQ1 channels. The completion of these aims will generate a better understanding of how KCNE beta subunits modulate KCNQ1 channel functions, how small molecule modulators affect KCNQ1 channels, and how the defects of disease- causing KCNQ1 mutations can be overcome in a mutation- and small molecule dependent manner. This would be a first step in generating mutation specific treatments of diseases, such as cardiac arrhythmias, caused by mutations in KCNQ1.

描述（由适用提供）：KCNQ1电压门控K+通道在许多不同的组织中表达，并且在这些不同的组织中扮演着巨大不同的作用。 KCNQ1中的突变和多态性已在多种疾病中隐含，包括心律不齐，遗传性死亡和对2型糖尿病的敏感性。在心脏中，KCNQ1与Beta亚基KCNE1共表达，形成了缓慢激活的电压门控IKS通道，这些通道对在细胞水平的心脏动作电位的存储库和电动员图的QT间隔产生了严重贡献。在其他细胞类型（例如上皮细胞和肾细胞）中，KCNQ1与β亚基KCNE2或KCNE3共表达，以形成对K+和CL-分泌很重要的电压独立的K+通道。 KCNQ1的关键作用已通过遗传突变揭示，这些突变与多样化的心律疾病有关，例如长QT综合征，短QT综合征和心房颤动。在许多情况下，与kcne1»亚基共同组装决定病理功能。不同的β亚基和突变如何改变KCNQ1通道的功能。我们将在这里只需测量KCNQ1通道中电压传感器和激活门的运动即可。这将使我们能够确定特定的β亚基或突变主要影响电压传感器还是栅极。我们还将测试KCNQ1对电压传感器运动和激活门的不同调节剂的影响，以了解这些分子如何影响KCNQ1活性以及这些分子是否可以恢复突变体KCNQ1通道的功能。这些目标的完成将更好地理解KCNE Beta亚基如何调节KCNQ1通道，以及如何以依赖突变和小分子的方式克服疾病的缺陷 - 引起KCNQ1突变。这将是由KCNQ1突变引起的疾病（例如心律不齐）的突变特异性治疗的第一步。