ArticleProceedings of the National Academy of Sciences of the United States of America2013
Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- Centipede Venom Peptides Acting on Ion Channels.Toxins · 2020Pooled it
- Identification of Sodium/Myo-Inositol Transporter 1 as a Major Determinant of Arterial Contractility.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Cannabidiol inhibits both human KActa pharmacologica Sinica · 2026Article
- Electro-Mechanical Uncoupling of KArchiv der Pharmazie · 2026Article
- Potassium channels in vascular smooth muscle cells.Physiological reviews · 2026Review
- A mechanistic understanding of how KCNE1 tunes KCNQ1 channel pharmacology.Structure (London, England : 1993) · 2026Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- Graded activation of mutant K41C-KCNE1:KCNQ1 channel complexes by mefenamic acid.Channels (Austin, Tex.) · 2025Article
- Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.Cell research · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.PNAS nexus · 2024Article
- Targeting the ICirculation research · 2024Article
- A generic binding pocket for small moleculeeLife · 2023Article
- Potassium voltage‑gated channel subfamily E member 4 facilitates the malignant progression of colon cancer by enhancing EGF containing fibulin extracellular matrix protein 2 expression.Experimental and therapeutic medicine · 2023Article
- Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention.PNAS nexus · 2023Article
- IBiomedicines · 2023Article
- Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1.Science advances · 2023Article
- A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.Pharmaceuticals (Basel, Switzerland) · 2022Article
- 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
- Kv Channel Ancillary Subunits: Where Do We Go from Here?Physiology (Bethesda, Md.) · 2022Review
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.