Modulation of KCNQ1 channel activity

描述(申请人提供)：KCNQ1电压门控K通道在许多不同的组织中表达，并在这些不同的组织中扮演着非常不同的角色。KCNQ1的突变和多态与多种疾病有关，包括心律失常、遗传性耳聋和2型糖尿病的易感性。在心脏中，KCNQ1与β亚基KCNE1共表达，形成缓慢激活的电压门控IKS通道，在细胞水平和心电图QT间期的复极中起关键作用。在其他类型的细胞中，如上皮细胞和肾脏细胞，KCNQ1与β亚基KCNE2或KCNE3共表达，形成一个电压无关的K通道，该通道对K和Cl-的分泌至关重要。KCNQ1的关键作用已被揭示为遗传突变，这些突变与各种心律紊乱有关，如长QT综合征、短QT综合征和心房颤动。在许多情况下，与KCNE1？亚基的共同组装决定了病理功能。不同的β亚基和突变如何改变KCNQ1通道的功能尚不完全清楚。这里我们将同时测量电压传感器和激活门在KCNQ1通道中的运动。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。我们还将测试KCNQ1的不同调节剂，包括激活剂和抑制剂，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的活性，以及这些分子是否能够恢复突变的KCNQ1通道的功能。这些目标的完成将使我们更好地理解KCNEβ亚基如何调节KCNQ1通道功能，小分子调节剂如何影响KCNQ1通道，以及如何以突变和小分子依赖的方式克服致病KCNQ1突变的缺陷。这将是产生针对KCNQ1突变引起的疾病(如心律失常)的突变特异性治疗的第一步。

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.