Modulation of KCNQ1 channel activity

KCNQ1 通道活性的调节

• 批准号: 8842668
• 负责人: ROBERT S KASS
• 金额: $ 32.92万
• 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/8842668
• 关键词: Action Potentials; Affect; Animals; Arrhythmia; Atrial Fibrillation; Basic Science; Cardiac; Clinical; Defect; Disease; Electrocardiogram; Epithelium; Future; Genetic Polymorphism; Heart; Heart Atrium; Inborn Genetic Diseases; 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 ß 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（由申请人提供）：KCNQ1电压门控K+通道在许多不同组织中表达，并且在这些不同组织中发挥广泛不同的作用。KCNQ1的突变和多态性与多种疾病有关，包括心律失常、遗传性耳聋和易感性。在心脏中，KCNQ1 与 β 亚基 KCNE1 共同表达，形成缓慢激活的电压。门控 IK 通道，对细胞水平上心脏动作电位的复极化和心电图 QT 间期起关键作用。 在其他细胞类型（如上皮细胞和肾细胞）中，KCNQ1 与 β 亚基 KCNE2 或 KCNE3 共表达。形成对 K+ 和 Cl- 分泌非常重要的电压依赖性 K+ 通道。与多种心律紊乱相关的遗传突变揭示了 KCNQ1 的关键作用。正如长 QT 综合征、短 QT 综合征和心房颤动一样，在许多情况下，与 KCNE1 β 亚基的共同组装决定了不同的 β 亚基和突变如何改变 KCNQ1 通道的功能。这里同时测量 KCNQ1 通道中电压传感器和激活门的运动，这将使我们能够确定特定的 β 亚基或突变是否主要影响电压传感器或门。还测试了KCNQ1的不同调节剂（激活剂和抑制剂）对电压传感器运动和激活门的影响，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这些突变KCNQ1通道的功能。目的将更好地了解 KCNE β 亚基如何调节 KCNQ1 通道功能、小分子调节剂 KCNQ1 通道如何以及引起疾病的 KCNQ1 突变缺陷如何影响以突变和小分子依赖性方式克服这一问题，这将是针对 KCNQ1 突变引起的疾病（例如心律失常）产生突变特异性治疗的第一步。