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by claude@2026-07, 2026-07-06
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The paper investigates how KCNE1 and KCNE3 subunits modulate KCNQ1 potassium channel gating that depends on phosphatidylinositol 4,5-bisphosphate (PIP2), particularly in the context of Gαq-coupled GPCR signaling. Using resolved structures of KCNQ1–KCNE1 and reassessed KCNQ1–KCNE3 structures with and without PIP2, the authors identify two PIP2-binding sites and show that KCNE1/3 contribute to an additional previously overlooked PIP2-related site involving residues critical for voltage-sensor and pore coupling. They find distinct effects: KCNE3 produces a voltage-insensitive, PIP2-gated channel governed by GPCR signaling, while KCNE1 increases PIP2 affinity and makes KCNQ1 more resistant to GPCR regulation, yielding channels that remain predominantly voltage-gated. The study explicitly frames these findings as mechanism for tissue-specific channel function, but it does not appear to include endometriosis- or adenomyosis-specific models. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
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 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 voltage sensor and pore domain coupling. 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 for tissue-specifically targeting multi-functional channels.
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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 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 voltage sensor and pore domain coupling. 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 for tissue-specifically targeting multi-functional channels.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
1. References 1 and 2 are removed from Abstract. 2. Affiliation of Washington University in St. Louis is uniformed. 3. Affiliation of KTH is detailed as KTH Royal Institute of Technology
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