Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Nat Commun. 2014 Apr 28;5:3750. doi: 10.1038/ncomms4750.
The functional properties of KCNQ1 channels are highly dependent on associated KCNE-β subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias and epilepsy. The mechanism by which KCNE1-β subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation.
KCNQ1 通道的功能特性高度依赖于相关的 KCNE-β 亚基。KCNQ1 或 KCNE 亚基的突变可导致先天性通道病，如耳聋、心律失常和癫痫。KCNE1-β 亚基减缓 KCNQ1 通道动力学的机制是当前争议的问题。在这里，我们表明 KCNQ1/KCNE1 通道的激活发生在两个步骤中：首先，四个 KCNQ1 亚基中相互独立的电压传感器运动产生主要的门控电荷运动，并构成 KCNQ1/KCNE1 电流激活时间过程中的初始延迟。其次，所有四个电压传感器和门的较慢和协调的构象变化，打开 KCNQ1/KCNE1 通道。我们的数据表明，KCNE1 将电压传感器的运动分为具有广泛不同电压依赖性和动力学的两个步骤。KCNQ1/KCNE1 通道中的两个电压传感器步骤可以通过药理学方法分离，并进一步通过致病突变分离。
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