Abstract
The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. A better understanding of the IKs channel (here called the KCNQ1/KCNE1 channel) properties and activities is of great importance to find the causes of LQTS and thus potentially treat LQTS. The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated potassium channels. The KCNQ1/KCNE1 channel consists of both the pore-forming subunit KCNQ1 and the modulatory subunit KCNE1. KCNE1 regulates the function of the KCNQ1 channel in several ways. This review aims to describe the current structural and functional knowledge about the cardiac KCNQ1/KCNE1 channel. In addition, we focus on the modulation of the KCNQ1/KCNE1 channel and its potential as a target therapeutic of LQTS.
Highlights
The cardiac IKs (KCNQ1/KCNE1) channel is one of the main contributors to the repolarizing currents that regulate the ventricular action potential duration (APD) and the QT interval in the electrocardiogram [1,2,3]
We have shown that Polyunsaturated Fatty Acid (PUFA) and their derivatives can enhance the activation of KCNQ1 and KCNQ1/KCNE1 channels by shifting the voltage dependence of current activation to more negative voltages and increasing the maximum conductance (Figure 4C) [18,116]
The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated K channels that are critical for cardiac excitability
Summary
The cardiac IKs (KCNQ1/KCNE1) channel is one of the main contributors to the repolarizing currents that regulate the ventricular action potential duration (APD) and the QT interval in the electrocardiogram [1,2,3]. A prolonged repolarization of the action potential caused by a loss of the IKs or IKr current is the most common cause for congenital LQTS-caused Torsades de pointes, ventricular fibrillation and sudden cardiac death (Figure 1C) [3,4]. Co-expression of KCNE1 slows the activation kinetics, increases the voltage-dependent current amplitude and shifts the voltage dependence of activation to more positive voltages of KCNQ1 channels in heterologous expression systems (Figure 3) [10,11] This slowing of the activation kinetics is very important for generating the slowly activating IKs currents that regulate the APD and QT interval. Comparing the structures between KCNQ1-CaM and KCNQ1/KCNE3-CaM, Mackinnon et al [35] found that KCNE3 lies in between S1, S4, S5 and S6 from three different subunits, suggesting KCNE1 and KCNE3 might share a similar location when associated with KCNQ1
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