PUFA stabilizes a conductive state of the selectivity filter in IKs channels

Alessia Golluscio, Jodene Eldstrom, Jessica J. Jowais, Marta Elena Perez, Kevin Peter Cunningham, Alicia De La Cruz, Xiaoan Wu, Valentina Corradi, D. Peter Tieleman, David Fedida and H. Peter Larsson 2024. PUFA stabilizes a conductive state of the selectivity filter in IKs channels. eLife. 13 RP95852. https://doi.org/10.7554/elife.95852

TitlePUFA stabilizes a conductive state of the selectivity filter in IKs channels
TypeJournal article
AuthorsAlessia Golluscio, Jodene Eldstrom, Jessica J. Jowais, Marta Elena Perez, Kevin Peter Cunningham, Alicia De La Cruz, Xiaoan Wu, Valentina Corradi, D. Peter Tieleman, David Fedida and H. Peter Larsson
Abstract

In cardiomyocytes, the KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause long QT syndrome (LQTS), a syndrome with a prolonged QT interval on the ECG, which increases the risk of ventricular arrhythmia and sudden cardiac death. One potential therapeutical intervention for LQTS is based on targeting IKs channels to restore channel function and/or the physiological QT interval. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and activate IKs channels by binding to two different sites, one in the voltage sensor domain – which shifts the voltage dependence to more negative voltages – and the other in the pore domain – which increases the maximal conductance of the channels (Gmax). However, the mechanism by which PUFAs increase the Gmax of the IKs channels is still poorly understood. In addition, it is unclear why IKs channels have a very small single-channel conductance and a low open probability or whether PUFAs affect any of these properties of IKs channels. Our results suggest that the selectivity filter in KCNQ1 is normally unstable, contributing to the low open probability, and that the PUFA-induced increase in Gmax is caused by a stabilization of the selectivity filter in an open-conductive state.

Article numberRP95852
JournaleLife
Journal citation13
ISSN2050-084X
Year2024
PublishereLife Sciences Publication
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.7554/elife.95852
PubMed ID39480699
Web address (URL)https://doi.org/10.7554/eLife.95852
Publication dates
Published31 Oct 2024

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