Four drug-sensitive subunits are required for maximal effect of a voltage sensor-targeted KCNQ opener

The Journal of General Physiology
Alice W WangHarley T Kurata

Abstract

KCNQ2-5 (Kv7.2-Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels but absent in the retigabine-insensitive KCNQ1 subtype. Recent work has demonstrated that certain KCNQ openers are insensitive to mutations of this conserved Trp, and that their effects are instead abolished or attenuated by mutations in the voltage-sensing domain (VSD). In this study, we investigate the stoichiometry of a VSD-targeted KCNQ2 channel activator, ICA-069673, by forming concatenated channel constructs with varying numbers of drug-insensitive subunits. In homomeric WT KCNQ2 channels, ICA-069673 strongly stabilizes an activated channel conformation, which is reflected in the pronounced deceleration of deactivation and leftward shift of the conductance-voltage relationship. A full complement of four drug-sensitive subunits is required for maximal sensitivity to ICA-069673-even a single drug-insensitive subunit leads to significantly weakened effects. In a companion article (see Yau et al. in this issue), we demonstrate very...Continue Reading

References

Aug 26, 1998·Methods in Enzymology·T M ShihA L Goldin
May 20, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Anne SchenzerMichael Schwake
Nov 2, 2005·Nature Reviews. Neuroscience·Patrick Delmas, David A Brown
Aug 15, 2006·Neuropharmacology·Bo Hjorth BentzenSøren-Peter Olesen
Sep 23, 2006·Science·Byung-Chang SuhBertil Hille
Apr 7, 2007·The Journal of Physiology·Byung-Chang Suh, Bertil Hille
Apr 11, 2007·Neurology·R J PorterUNKNOWN 205 Study Group
Dec 7, 2007·Current Opinion in Pharmacology·Francesco MiceliMaurizio Taglialatela
Jan 22, 2008·Trends in Pharmacological Sciences·Qiaojie XiongMin Li
Apr 16, 2008·The Journal of General Physiology·Jon T SackJ Oliver Dolly
Mar 21, 2009·British Journal of Pharmacology·David A Brown, Gayle M Passmore
Sep 8, 2009·Neuroscience Letters·Karen PadillaKen McCormack
Aug 18, 2010·Proceedings of the National Academy of Sciences of the United States of America·Asher PeretzBernard Attali
Aug 18, 2010·Pharmacology·Sigrid Marie BlomHenrik Sindal Jensen
Oct 15, 2010·Neurology·M J BrodieUNKNOWN RESTORE 2 Study Group
Apr 18, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jeremiah D OsteenH Peter Larsson
Jun 13, 2012·The Journal of General Physiology·Vsevolod TelezhkinAlasdair J Gibb
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Daniel WerryDavid Fedida
Feb 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Francesco MiceliMaurizio Taglialatela
Jul 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Mark A ZaydmanJianmin Cui
Sep 4, 2015·Nature Communications·Robin Y KimHarley T Kurata
Aug 11, 2016·The Journal of Physiology·Alice W WangHarley T Kurata
Oct 11, 2017·Annual Review of Pharmacology and Toxicology·Vincenzo BarreseIain A Greenwood
Oct 13, 2017·Current Medicinal Chemistry·Francesco MiceliMaurizio Taglialatela
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Robin Y KimHarley T Kurata
Sep 1, 2018·The Journal of General Physiology·Michael C YauHarley T Kurata

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Citations

Oct 31, 2018·The Journal of General Physiology·Caroline K WangHarley T Kurata
Jul 12, 2020·Epilepsia·Richard KanyoHarley T Kurata
Sep 1, 2018·The Journal of General Physiology·Michael C YauHarley T Kurata
May 8, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Fan ZhangKeWei Wang
Oct 22, 2019·Assay and Drug Development Technologies·Benjamin WilenkinBirgit T Priest
Dec 19, 2020·Epilepsia Open·Jasmine MagheraHarley T Kurata
Jun 25, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Lance H RodanVandana Shashi

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Methods Mentioned

BETA
PCR
transfection
electrophoresis
restriction digests

Software Mentioned

MODEL
ICA73
SWISS
pClamp

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