Modulation of KCNQ1 channel activity

描述（由申请人提供）：KCNQ 1电压门控K+通道在许多不同组织中表达，并在这些不同组织中发挥广泛不同的作用。KCNQ 1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2型糖尿病易感性。在心脏中，KCNQ 1与β亚基KCNE 1共表达，形成缓慢激活的电压门控IKs通道，该通道在细胞水平上对心脏动作电位的复极化和心电图的QT间期起关键作用。在其他细胞类型中，如上皮细胞和肾细胞，KCNQ 1与β亚基KCNE 2或KCNE 3共表达，形成电压非依赖性K+通道，对K+和Cl-分泌很重要。KCNQ 1的关键作用已被遗传突变所揭示，这些突变与长QT综合征、短QT综合征和心房颤动等多种心律失常有关。在许多情况下，与KCNE 1 β亚基的共组装决定了病理功能。不同的β亚基和突变如何改变KCNQ 1通道的功能尚不完全清楚。在这里，我们将同时测量KCNQ 1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。我们还将测试KCNQ 1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KCNQ 1活性以及这些分子是否可以恢复突变KCNQ 1通道的功能。这些目标的完成将使我们更好地理解KCNE β亚基如何调节KCNQ 1通道功能，小分子调节剂如何影响KCNQ 1通道，以及如何以突变和小分子依赖的方式克服致病KCNQ 1突变的缺陷。这将是产生突变特异性治疗疾病的第一步，例如由KCNQ 1突变引起的心律失常。

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.