A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation.

Communications Biology
Yongfeng LiuJianmin Cui

Abstract

KCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

References

Apr 1, 1992·The Journal of Physiology·J GaoG J Baldo
Oct 31, 2002·The Journal of General Physiology·Zhe LuYajamana Ramu
Jan 11, 2003·Science·Yi-Han ChenWei Huang
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
May 20, 2005·Nature·Yoshimichi MurataYasushi Okamura
Jul 9, 2005·Science·Stephen B LongRoderick Mackinnon
Sep 24, 2005·The Journal of Physiology·Koichi Nakajo, Yoshihiro Kubo
Sep 27, 2005·Physiological Reviews·Jeanne M Nerbonne, Robert S Kass
Oct 28, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yang LiMark S Shapiro
Nov 2, 2005·Nature Reviews. Neuroscience·Patrick Delmas, David A Brown
Sep 23, 2006·Science·Byung-Chang SuhBertil Hille
Nov 1, 2006·The Journal of General Physiology·Phillip PianSteven A Siegelbaum
Dec 1, 2006·Nature·Daniel SchmidtRoderick MacKinnon
Apr 7, 2007·The Journal of Physiology·Byung-Chang Suh, Bertil Hille
May 13, 2009·Journal of Chemical Information and Modeling·Mikko J VainioMark S Johnson
Oct 28, 2009·The Journal of General Physiology·Ciria C HernandezMark S Shapiro
Oct 29, 2009·Human Mutation·Paula L HedleyMichael Christiansen
May 19, 2010·The Journal of General Physiology·Dick WuJianmin Cui
Jul 9, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Juan Camilo Gómez-PosadaAlvaro Villarroel
Nov 19, 2010·The Journal of Biological Chemistry·Alison M ThomasAndrew Tinker
Nov 30, 2010·Biophysical Journal·Dick WuJianmin Cui
Dec 15, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jeremiah D OsteenRobert S Kass
Feb 16, 2011·Biophysical Journal·Li-Juan MaVitya Vardanyan
Mar 24, 2011·Nature Communications·Hui ZhengQiu-Xing Jiang
May 18, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yang LiJianmin Cui
Dec 3, 2011·The Journal of Comparative Neurology·Chih H King, Steven S Scherer
Feb 4, 2012·The Journal of Biological Chemistry·Vsevolod TelezhkinDavid A Brown

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Citations

Dec 17, 2020·International Journal of Molecular Sciences·Xiaoan Wu, H Peter Larsson
May 16, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yangyang LinJianmin Cui
Jun 18, 2021·Journal of Molecular Biology·Tanadet PipatpolkaiPhillip J Stansfeld
Jun 27, 2021·European Journal of Pharmacology·Moawiah M Naffaa, Ola A Al-Ewaidat
Oct 16, 2021·Communications Biology·Shashank PantEmad Tajkhorshid

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Software Mentioned

Clampex
Pulse acquisition
Patchmaster
IGOR
SigmaPlot
ShaEP
MODELLER
Clampfit
MDock
HEKA

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