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bioRxiv · 10.1101/2025.06.08.658478

Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function

Cui, C.·Zhao, L.·Kermani, A. A.·Du, S.·Pipatpolkai, T.·Jiang, M.·Chittori, S.·Tan, Y.·Shi, J.·Delemotte, L.·Cui, J.·Sun, J.
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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 Gq-coupled GPCR activation. While modulation of KCNQ1s 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 KCNQ1s 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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Cui, C., Zhao, L., Kermani, A. A., Du, S., Pipatpolkai, T., Jiang, M., Chittori, S., Tan, Y., Shi, J., Delemotte, L., Cui, J., Sun, J.. 2025-06-08. Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function. https://doi.org/10.1101/2025.06.08.658478

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