Inactivation of KCNQ1 Potassium Channels Reveals Dynamic Coupling Between Voltage Sensing and Pore Opening

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Nov 24

PMID 29167462

Citations 42

Authors

Panpan Hou

Jodene Eldstrom

Jingyi Shi

Ling Zhong

Kelli McFarland

Yuan Gao

David Fedida

Jianmin Cui

Affiliations

Soon will be listed here.

Abstract

In voltage-activated ion channels, voltage sensor (VSD) activation induces pore opening via VSD-pore coupling. Previous studies show that the pore in KCNQ1 channels opens when the VSD activates to both intermediate and fully activated states, resulting in the intermediate open (IO) and activated open (AO) states, respectively. It is also well known that accompanying KCNQ1 channel opening, the ionic current is suppressed by a rapid process called inactivation. Here we show that inactivation of KCNQ1 channels derives from the different mechanisms of the VSD-pore coupling that lead to the IO and AO states, respectively. When the VSD activates from the intermediate state to the activated state, the VSD-pore coupling has less efficacy in opening the pore, producing inactivation. These results indicate that different mechanisms, other than the canonical VSD-pore coupling, are at work in voltage-dependent ion channel activation.

Citing Articles

The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.

Hou P, Zhao L, Zhong L, Shi J, Wang H, Gao J PNAS Nexus. 2024; 3(10):pgae452.

PMID: 39434867 PMC: 11492796. DOI: 10.1093/pnasnexus/pgae452.

Targeting the I Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants.

Zhong L, Yan Z, Jiang D, Weng K, Ouyang Y, Zhang H Circ Res. 2024; 135(7):722-738.

PMID: 39166328 PMC: 11392204. DOI: 10.1161/CIRCRESAHA.124.325009.

Modulation of potassium channels by transmembrane auxiliary subunits via voltage-sensing domains.

Nakajo K, Kasuya G Physiol Rep. 2024; 12(6):e15980.

PMID: 38503563 PMC: 10950684. DOI: 10.14814/phy2.15980.

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors.

Fedida D, Sastre D, Dou Y, Westhoff M, Eldstrom J J Gen Physiol. 2024; 156(3).

PMID: 38294435 PMC: 10829594. DOI: 10.1085/jgp.202313465.

Arrhythmia-associated calmodulin variants interact with KCNQ1 to confer aberrant membrane trafficking and function.

Kang P, Woodbury L, Angsutararux P, Sambare N, Shi J, Marras M PNAS Nexus. 2023; 2(11):pgad335.

PMID: 37965565 PMC: 10642763. DOI: 10.1093/pnasnexus/pgad335.

References

Sanguinetti M, Curran M, Zou A, Shen J, Spector P, Atkinson D . Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996; 384(6604):80-3. DOI: 10.1038/384080a0. View

Lu Z, Klem A, Ramu Y . Coupling between voltage sensors and activation gate in voltage-gated K+ channels. J Gen Physiol. 2002; 120(5):663-76. PMC: 2229552. DOI: 10.1085/jgp.20028696. View

Pardo L, Heinemann S, Terlau H, Ludewig U, Lorra C, Pongs O . Extracellular K+ specifically modulates a rat brain K+ channel. Proc Natl Acad Sci U S A. 1992; 89(6):2466-70. PMC: 48679. DOI: 10.1073/pnas.89.6.2466. View

Liu Y, Holmgren M, Jurman M, Yellen G . Gated access to the pore of a voltage-dependent K+ channel. Neuron. 1997; 19(1):175-84. DOI: 10.1016/s0896-6273(00)80357-8. View

Brown D . Kv7 (KCNQ) potassium channels that are mutated in human diseases. J Physiol. 2008; 586(7):1781-3. PMC: 2375729. DOI: 10.1113/jphysiol.2008.153007. View

Osteen J, Gonzalez C, Sampson K, Iyer V, Rebolledo S, Larsson H . KCNE1 alters the voltage sensor movements necessary to open the KCNQ1 channel gate. Proc Natl Acad Sci U S A. 2010; 107(52):22710-5. PMC: 3012494. DOI: 10.1073/pnas.1016300108. View

Ledwell J, Aldrich R . Mutations in the S4 region isolate the final voltage-dependent cooperative step in potassium channel activation. J Gen Physiol. 1999; 113(3):389-414. PMC: 2222902. DOI: 10.1085/jgp.113.3.389. View

Long S, Campbell E, MacKinnon R . Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science. 2005; 309(5736):903-8. DOI: 10.1126/science.1116270. View

Shen H, Zhou Q, Pan X, Li Z, Wu J, Yan N . Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science. 2017; 355(6328). DOI: 10.1126/science.aal4326. View

10.

Lee S, Banerjee A, MacKinnon R . Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+) channels. PLoS Biol. 2009; 7(3):e47. PMC: 2650729. DOI: 10.1371/journal.pbio.1000047. View

11.

Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M . Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature. 2016; 537(7619):191-196. DOI: 10.1038/nature19321. View

12.

Chen J, Mitcheson J, Tristani-Firouzi M, Lin M, Sanguinetti M . The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Proc Natl Acad Sci U S A. 2001; 98(20):11277-82. PMC: 58720. DOI: 10.1073/pnas.201250598. View

13.

Boulet I, Labro A, Raes A, Snyders D . Role of the S6 C-terminus in KCNQ1 channel gating. J Physiol. 2007; 585(Pt 2):325-37. PMC: 2375480. DOI: 10.1113/jphysiol.2007.145813. View

14.

Pusch M, Bertorello L, Conti F . Gating and flickery block differentially affected by rubidium in homomeric KCNQ1 and heteromeric KCNQ1/KCNE1 potassium channels. Biophys J. 2000; 78(1):211-26. PMC: 1300631. DOI: 10.1016/S0006-3495(00)76586-6. View

15.

Lopez-Barneo J, Hoshi T, Heinemann S, Aldrich R . Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels. Recept Channels. 1993; 1(1):61-71. View

16.

Starkus J, Kuschel L, RAYNER M, Heinemann S . Ion conduction through C-type inactivated Shaker channels. J Gen Physiol. 1997; 110(5):539-50. PMC: 2229384. DOI: 10.1085/jgp.110.5.539. View

17.

Pusch M, Ferrera L, Friedrich T . Two open states and rate-limiting gating steps revealed by intracellular Na+ block of human KCNQ1 and KCNQ1/KCNE1 K+ channels. J Physiol. 2001; 533(Pt 1):135-43. PMC: 2278592. DOI: 10.1111/j.1469-7793.2001.0135b.x. View

18.

Tristani-Firouzi M, Sanguinetti M . Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits. J Physiol. 1998; 510 ( Pt 1):37-45. PMC: 2231024. DOI: 10.1111/j.1469-7793.1998.037bz.x. View

19.

Hoshi T, Zagotta W, Aldrich R . Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science. 1990; 250(4980):533-8. DOI: 10.1126/science.2122519. View

20.

Pusch M . Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK. Pflugers Arch. 1998; 437(1):172-4. DOI: 10.1007/s004240050765. View