ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state.
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
06 12 2021
06 12 2021
Historique:
received:
19
05
2021
revised:
16
07
2021
accepted:
15
09
2021
entrez:
12
10
2021
pubmed:
13
10
2021
medline:
26
10
2021
Statut:
ppublish
Résumé
KCNQ1 is a pore-forming K+ channel subunit critically important to cardiac repolarization at high heart rates. (2R)-N-[4-(4-methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2 piperidinecarboxamide, or ML277, is an activator of this channel that rescues function of pathophysiologically important mutant channel complexes in human induced pluripotent stem cell-derived cardiomyocytes, and that therefore may have therapeutic potential. Here we extend our understanding of ML277 actions through cell-attached single-channel recordings of wild-type and mutant KCNQ1 channels with voltage sensor domains fixed in resting, intermediate, and activated states. ML277 has profound effects on KCNQ1 single-channel kinetics, eliminating the flickering nature of the openings, converting them to discrete opening bursts, and increasing their amplitudes approximately threefold. KCNQ1 single-channel behavior after ML277 treatment most resembles IO state-locked channels (E160R/R231E) rather than AO state channels (E160R/R237E), suggesting that at least during ML277 treatment, KCNQ1 does not frequently visit the AO state. Introduction of KCNE1 subunits reduces the effectiveness of ML277, but some enhancement of single-channel openings is still observed.
Identifiants
pubmed: 34636894
pii: 212696
doi: 10.1085/jgp.202112969
pmc: PMC8515649
pii:
doi:
Substances chimiques
(R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide
0
KCNQ1 Potassium Channel
0
KCNQ1 protein, human
0
Piperidines
0
Potassium Channels, Voltage-Gated
0
Thiazoles
0
Tosyl Compounds
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : PJT-156181
Pays : Canada
Informations de copyright
© 2021 Eldstrom et al.
Références
Br J Pharmacol. 1997 Sep;122(2):187-9
pubmed: 9313924
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5936-41
pubmed: 22910039
J Physiol. 2019 Feb;597(3):723-740
pubmed: 30412286
Heart Rhythm. 2015 Feb;12(2):386-94
pubmed: 25444851
Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13180-5
pubmed: 23861489
Islets. 2014;6(4):e962386
pubmed: 25437377
PLoS One. 2009;4(1):e4236
pubmed: 19156197
EMBO J. 2003 Oct 15;22(20):5412-21
pubmed: 14532114
Nature. 1996 Nov 7;384(6604):78-80
pubmed: 8900282
J Physiol. 2015 Jun 15;593(12):2605-15
pubmed: 25653179
Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7879-7888
pubmed: 30918124
Neuron. 2018 Feb 21;97(4):836-852.e6
pubmed: 29429937
J Physiol. 2001 May 15;533(Pt 1):135-43
pubmed: 11351022
Mol Pharmacol. 2020 Feb;97(2):132-144
pubmed: 31722973
Elife. 2016 Jan 23;5:
pubmed: 26802629
Nat Rev Dis Primers. 2020 Jul 16;6(1):58
pubmed: 32678103
Biophys J. 1998 Aug;75(2):785-92
pubmed: 9675180
Elife. 2020 Feb 25;9:
pubmed: 32096762
Biophys J. 2011 Feb 16;100(4):885-94
pubmed: 21320432
Front Pharmacol. 2012 Jul 27;3:145
pubmed: 22866036
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):E996-1005
pubmed: 23431135
Circ Res. 2006 Apr 28;98(8):1055-63
pubmed: 16556865
Elife. 2019 Jul 22;8:
pubmed: 31329101
J Physiol. 1998 Jul 1;510 ( Pt 1):37-45
pubmed: 9625865
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22710-5
pubmed: 21149716
Nat Commun. 2017 Nov 23;8(1):1730
pubmed: 29167462
J Physiol. 2003 Oct 15;552(Pt 2):369-78
pubmed: 14561821
Cell. 2017 Jun 1;169(6):1042-1050.e9
pubmed: 28575668
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8732-7
pubmed: 23650380
J Gen Physiol. 2017 Aug 7;149(8):781-798
pubmed: 28687606
Elife. 2014 Dec 23;3:e03606
pubmed: 25535795
Biophys J. 2004 Mar;86(3):1454-69
pubmed: 14990473
Biophys J. 2006 Mar 15;90(6):2235-44
pubmed: 16326905
Proc Natl Acad Sci U S A. 2012 May 1;109(18):7103-8
pubmed: 22509038
Mol Pharmacol. 1998 Jul;54(1):220-30
pubmed: 9658209
EMBO J. 1999 Aug 2;18(15):4137-48
pubmed: 10428953
Heart Rhythm. 2018 Oct;15(10):1566-1574
pubmed: 29857160
Biophys J. 2017 Jul 25;113(2):415-425
pubmed: 28746852
Cell. 2020 Jan 23;180(2):340-347.e9
pubmed: 31883792
Stem Cell Res Ther. 2015 Mar 19;6:39
pubmed: 25889101
Biophys J. 2007 Dec 15;93(12):4159-72
pubmed: 17704175
J Gen Physiol. 2011 Nov;138(5):521-35
pubmed: 22042987
Circ Res. 2006 Apr 28;98(8):1048-54
pubmed: 16556866
Nature. 1996 Nov 7;384(6604):80-3
pubmed: 8900283
Nat Commun. 2020 Feb 3;11(1):676
pubmed: 32015334
J Biol Chem. 2001 Apr 27;276(17):13600-5
pubmed: 11278406
Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7367-E7376
pubmed: 28808020
PLoS One. 2012;7(12):e51820
pubmed: 23251633
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9095-100
pubmed: 21576493
Biophys J. 2015 Jan 6;108(1):62-75
pubmed: 25564853
Nat Commun. 2014 Apr 28;5:3750
pubmed: 24769622
J Biol Chem. 2008 Aug 15;283(33):22649-58
pubmed: 18490447
Biophys J. 2007 Apr 15;92(8):2747-56
pubmed: 17237198