Journal article
Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel
Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2517495123
01/20/2026
DOI: 10.1073/pnas.2517495123
PMCID: PMC12818427
PMID: 41543902
Abstract
Kv7.1 is a cardiac voltage-gated potassium channel that underlies the delayed rectifier current (IKS) in the heart. The slow response to membrane depolarization is a hallmark feature of this channel’s physiology, yet the mechanistic basis of how voltage promotes the open potassium conducting state is unknown. We focused on previously identified aromatic residues which might couple the pore and voltage-sensing domains (VSDs) by using a chemical tuning approach whereby aromatic residues are modified by serial fluorination. The data show that serial fluorination at one site (F232 on the S4 helix, within the VSD) resulted in a stepwise voltage-gating shift, where each added fluorine atom further biased channel opening to more negative voltages. Mutant-cycle analysis of proximal positively charged amino acids indicates that F232 likely forms a cation–π interaction with K285, a residue at the tip of the S5 segment in the pore domain. Using cryoelectron microscopy, a partial structure of the F232 penta-F-Phe Kv7.1 (KCNQ1) open channel was resolved to 6 Å. The data support a gating mechanism whereby the F232–K285 cation–π interaction represents an intermediate activated state that is broken prior to channel opening.
Details
- Title: Subtitle
- Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel
- Creators
- Miranda E Schene - University of IowaChristopher A Ahern - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2517495123
- DOI
- 10.1073/pnas.2517495123
- PMID
- 41543902
- PMCID
- PMC12818427
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R35148239 / HHS | NIH | National Institute of General Medical Sciences (NIGMS) F30HL165692 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- Language
- English
- Date published
- 01/20/2026
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9985121482302771
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