ArticleThe Journal of general physiology2021
ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Electrophysiological characterization of the state-dependent inhibition of Kv7.1 and IMolecular pharmacology · 2025Article
- A physiologically-relevant intermediate state structure of a voltage-gated potassium channel.Nature communications · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
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- Targeting the ICirculation research · 2024Article
- A new twist to increase ion flow.Nature chemical biology · 2024Article
- Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors.The Journal of general physiology · 2024Article
- A generic binding pocket for small moleculeeLife · 2023Article
- Emerging methods to model cardiac ion channel and myocyte electrophysiology.Biophysics reviews · 2023Review
- Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.Nature communications · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
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.
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