ArticleCell research2025
Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function.
Article in Cell research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Structural and kinetic mechanisms of state-dependent potassium channel inhibition.Science advances · 2026Article
- Article
- The SIMDA framework maps PIP2-binding sites regulating the KCNQ1 channel.Nature communications · 2026Article
- Article
- Barium senses subtle pore changes in a voltage-gated KScience advances · 2026Article
- C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Cannabidiol inhibits both human KActa pharmacologica Sinica · 2026Article
- PIPNature communications · 2026Article
- A mechanistic understanding of how KCNE1 tunes KCNQ1 channel pharmacology.Structure (London, England : 1993) · 2026Article
- High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.JCI insight · 2026Article
- Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the KProceedings of the National Academy of Sciences of the United States of America · 2026Article
- PIPResearch square · 2025Article
- High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants.bioRxiv : the preprint server for biology · 2025Article
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Abstract
KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE family subunits (KCNE1-5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1's voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1-KCNE1 and reassessed the reported KCNQ1-KCNE3 structures with and without PIP2. We revealed that KCNQ1-KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for coupling voltage sensor and pore domains. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1's PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights into tissue-specifically targeting multi-functional channels.
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