title: Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels.
abstract: Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1-KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1-KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1)4(KCNE1)n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or IKs, is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether IKs is mediated by KCNE-saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments IKs current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1)4(KCNE1)n channels are present as components of IKs and are pharmacologically distinct from KCNE-saturated KCNQ1-KCNE1 channels.
authors: The Solomon H Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Haibo
authors: H
authors: Yu
authors: Zhihong
authors: Z
authors: Lin
authors: Margrith E
authors: ME
authors: Mattmann
authors: Beiyan
authors: B
authors: Zou
authors: Cecile
authors: C
authors: Terrenoire
authors: Hongkang
authors: H
authors: Zhang
authors: Meng
authors: M
authors: Wu
authors: Owen B
authors: OB
authors: McManus
authors: Robert S
authors: RS
authors: Kass
authors: Craig W
authors: CW
authors: Lindsley
authors: Corey R
authors: CR
authors: Hopkins
authors: Min
authors: M
authors: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology*
chemical_list: C576869:(R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D013844:Thiazoles; D014105:Tosyl Compounds; D011188:Potassium
keywords: cardiac physiology; drug; long QT; pharmacology
references: Cardiovasc Res. 2005 Aug 15;67(3):529-38
references: 16039274
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3128-33
references: 18272489
references: Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11866-71
references: 22745159
references: J Physiol. 2011 Dec 15;589(Pt 24):6093-104
references: 22025662
references: PLoS One. 2012;7(12):e51820
references: 23251633
references: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18862-7
references: 20962273
references: Hum Mutat. 2009 Nov;30(11):1486-511
references: 19862833
references: J Physiol. 1952 Aug;117(4):500-44
references: 12991237
references: Neuron. 2003 Sep 25;40(1):15-23
references: 14527430
references: J Gen Physiol. 2012 Feb;139(2):135-44
references: 22250012
references: Am J Physiol Cell Physiol. 2001 Feb;280(2):C359-72
references: 11208532
references: J Physiol. 2007 Jul 15;582(Pt 2):675-93
references: 17478540
references: J Neurosci. 2005 May 18;25(20):5051-60
references: 15901787
references: Mol Pharmacol. 2000 Sep;58(3):591-600
references: 10953053
references: J Physiol. 1998 Jul 1;510 ( Pt 1):37-45
references: 9625865
references: Pediatr Cardiol. 2012 Aug;33(6):938-42
references: 22421958
references: Nat Chem Biol. 2007 May;3(5):287-96
references: 17435769
references: Neuron. 1995 Jun;14(6):1303-9
references: 7605639
references: Physiology (Bethesda). 2011 Oct;26(5):365-76
references: 22013194
references: Mol Pharmacol. 1998 Jul;54(1):220-30
references: 9658209
references: Acta Pharmacol Sin. 2003 Jul;24(7):681-6
references: 12852835
references: Bioorg Med Chem Lett. 2012 Sep 15;22(18):5936-41
references: 22910039
references: Acta Pharmacol Sin. 2008 Jun;29(6):653-60
references: 18501111
references: Circ Res. 2003 Nov 14;93(10):941-7
references: 14576198
references: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18751-2
references: 20974964
references: Epilepsia. 2012 Mar;53(3):412-24
references: 22220513
references: Neuropharmacology. 2001 Jun;40(7):888-98
references: 11378159
references: Cardiovasc Res. 1998 May;38(2):441-50
references: 9709405
references: Nature. 1996 Nov 7;384(6604):80-3
references: 8900283
references: Trends Pharmacol Sci. 2008 Feb;29(2):99-107
references: 18206251
references: Br J Pharmacol. 2001 Jan;132(2):381-4
references: 11159685
references: J Biol Chem. 1998 Dec 18;273(51):34069-74
references: 9852064
references: Mol Pharmacol. 2005 Apr;67(4):1009-17
references: 15662042
references: J Mol Cell Cardiol. 2005 Feb;38(2):277-87
references: 15698834
references: Neuron. 2004 Jun 24;42(6):927-37
references: 15207237
references: J Biol Chem. 2008 Aug 15;283(33):22649-58
references: 18490447
references: Sci Transl Med. 2009 Oct 14;1(2):2ra6
references: 20368164
references: J Physiol. 2008 Apr 1;586(7):1785-9
references: 18174212
references: J Gen Physiol. 1994 Jul;104(1):87-105
references: 7964597
references: Nat Genet. 1996 Jan;12(1):17-23
references: 8528244
references: PLoS One. 2009;4(1):e4236
references: 19156197
references: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1478-82
references: 18223154
references: Nature. 1996 Nov 7;384(6604):78-80
references: 8900282
references: Nat Rev Drug Discov. 2009 Dec;8(12):982-1001
references: 19949402