Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel

Miranda E Schene; Christopher A Ahern

doi:10.1073/pnas.2517495123

Back

Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel

Journal article

Open access

Peer reviewed

Chemical tuning reveals a cation-π gating bridge between the voltage-sensor and pore domains in the K v 7.1 potassium channel

Miranda E Schene and Christopher A Ahern

Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2517495123

01/20/2026

DOI: 10.1073/pnas.2517495123

PMCID: PMC12818427

PMID: 41543902

Files and links (1)

url

https://doi.org/10.1073/pnas.2517495123View

Published (Version of record) Open Access

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.

Animals

Cations - chemistry

Cations - metabolism

Cryoelectron Microscopy

Humans

Ion Channel Gating - physiology

KCNQ1 Potassium Channel - chemistry

KCNQ1 Potassium Channel - genetics

KCNQ1 Potassium Channel - metabolism

Models, Molecular

Protein Domains

Rats

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 Iowa
Christopher 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

Metrics

15 Record Views