Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Dec 11;21(24):9440.
doi: 10.3390/ijms21249440.

Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

Xiaoan Wu  1 , H Peter Larsson  1
Affiliations
Review

Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

Xiaoan Wu et al. Int J Mol Sci. .

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.

Keywords: ATP; IKs; KCNE1; KCNQ1; Kv channel; PIP2; PKA; PUFA; cardiac arrhythmias; long QT syndrome.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Long QT syndrome (LQTS) caused by a loss of the IKs current. Normal electrocardiogram, ventricular action potential and IKs current are depicted by black solid lines. The electrocardiogram, ventricular action potential and IKs current associated with LQTS are depicted by red dashed lines. Horizontal and vertical axes are not shown for clarity. (A) The electrocardiogram consists of five waves: P, Q, R, S and T waves. The P wave represents the depolarization of the atria. The QRS complex represents the rapid ventricular depolarization. The T wave represents the repolarization of the ventricles. The QT interval is the interval from the beginning of the Q wave to the end of the T wave. Patients with a prolonged QT interval can cause LQTS. Action potential duration is indicated. (B) The ventricular action potential consists of five phases, phase 0 to phase 4. Phase 0 is the depolarization phase that is mediated by an inward Na+ current. Phase 1 is mainly mediated by a transient outward K+ current. Phase 2 is the plateau phase that is mainly mediated by an inward Ca2+ current and outward K+ current. Phase 3 is the repolarization phase that is mainly mediated by outward K+ (IKs in green and IKr) currents. Phase 4 is mainly mediated by an outward K+ current (IK1). (C) The IKs current underlies the repolarization of the ventricular action potential, shown as phase 3 in (B).
Figure 2
Figure 2
Topology of KCNQ1 and KCNE1. In the KCNQ1 subunit, S1–S4 transmembrane segments form the peripheral voltage-sensor domain (VSD) in blue and S5–S6 transmembrane segments form the central pore domain (PD) in pink. The KCNE1 subunit is one single transmembrane segment in orange. (A) Schematic side view of one KCNQ1 subunit and one KCNE1 subunit. The white plus symbol in S4 represents the positive gating charges. (B) Schematic top view of a tetrameric KCNQ1 channel with only two KCNE1 subunits. The number of the KCNE1 subunit varies from 1 to 4. KCNE1 is located in between S1, S4 and S6 from KCNQ1. Red dashed line indicates putative interactions between KCNE1 and S1, S4 and S6 from KCNQ1. A VSD (green circle) from one subunit is adjacent to a PD (purple oval) from its neighboring subunit.
Figure 3
Figure 3
Voltage-clamp fluorometry recordings of KCNQ1 and KCNQ1/KCNE1 channels. (A) Representative current (black) and fluorescence (red) traces from KCNQ1 and KCNQ1/KCNE1 channels in response to the indicated voltage protocol (right). Cells are held at −120 mV and stepped to voltages between −140 (−160 mV for fluorescence) and +80 mV in +20 mV followed by a step to −40 mV. (B) Voltage dependence of currents (black) and fluorescence (red) from KCNQ1 (squares) and KCNQ1/KCNE1 (circles) channels. KCNE1 shifts the voltage dependence of the current activation of KCNQ1 to more positive voltages and separates the voltage sensors movement of KCNQ1. This suggests that S4 in KCNQ1/KCNE1 moves in two steps.
Figure 4
Figure 4
Effects of N-arachidonoyl taurine (N-AT) on cardiac KCNQ1/KCNE1 channels. (A) Structure of the polyunsaturated fatty acid (PUFA) analog N-AT with a negatively charged head group and a hydrophobic tail group. (B) Representative current traces from KCNQ1/KCNE1 channels in 0 μM N-AT (black) and 70 μM N-AT (red) in response to the indicated voltage protocol. Cells are held at −80 mV and stepped to voltages between −90 and +50 mV in +10 mV followed by a step to −30 mV. Arrows indicate the tail currents. (C) Voltage dependence of currents from KCNQ1/KCNE1 channels in 0 μM N-AT (black) and 70 μM N-AT (red) indicating an increased maximum conductance and negative shift of voltage dependence. Normalized voltage dependence of KCNQ1/KCNE1 channels in 70 μM N-AT is indicated as a red dashed line. (D) Illustration of the lipoelectric mechanism. Schematic side view (left) of KCNQ1/KCNE1 channels with S4 (blue), S6 (pink) and KCNE1 (orange). Electrostatic interaction between the negatively charged PUFA head group (red) and positive charges (white plus symbol) in S4. Schematic top view (right) of a tetrameric KCNQ1 channel with only two KCNE1 subunits. Electrostatic interaction between the negatively charged PUFA head group (red) and positively charged K326 (white plus symbol).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Shih H.T. Anatomy of the action potential in the heart. Tex. Heart Inst. J. 1994;21:30–41. - PMC - PubMed
    1. Klabunde R.E. Cardiac electrophysiology: Normal and ischemic ionic currents and the ECG. Adv. Physiol. Educ. 2017;41:29–37. doi: 10.1152/advan.00105.2016. - DOI - PubMed
    1. Nerbonne J.M., Kass R.S. Molecular physiology of cardiac repolarization. Physiol. Rev. 2005;85:1205–1253. doi: 10.1152/physrev.00002.2005. - DOI - PubMed
    1. Vincent G.M. The long QT syndrome. Indian Pacing Electrophysiol. J. 2002;2:127–142. - PMC - PubMed
    1. Schwartz P.J., Crotti L., Insolia R. Long-QT syndrome: From genetics to management. Circ. Arrhythm. Electrophysiol. 2012;5:868–877. doi: 10.1161/CIRCEP.111.962019. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources