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

Autor:	Golluscio A; Department of Physiology and Biophysics, University of Miami, Miami, United States.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden., Eldstrom J; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada., Jowais JJ; Department of Physiology and Biophysics, University of Miami, Miami, United States., Perez ME; Department of Physiology and Biophysics, University of Miami, Miami, United States., Cunningham KP; Department of Physiology and Biophysics, University of Miami, Miami, United States.; School of Life Sciences, University of Westminster, London, United Kingdom., De La Cruz A; Department of Physiology and Biophysics, University of Miami, Miami, United States.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden., Wu X; Department of Physiology and Biophysics, University of Miami, Miami, United States., Corradi V; Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Canada., Tieleman DP; Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Canada., Fedida D; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada., Larsson HP; Department of Physiology and Biophysics, University of Miami, Miami, United States.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Oct 31; Vol. 13. Date of Electronic Publication: 2024 Oct 31.
DOI:	10.7554/eLife.95852
Abstrakt:	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. Competing Interests: AG, JE, JJ, MP, KC, AD, XW, VC, DT, DF, HL No competing interests declared (© 2024, Golluscio et al.)
Databáze:	MEDLINE
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