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
| Title | PUFA stabilizes a conductive state of the selectivity filter in IKs channels |
|---|---|
| Type | Journal article |
| Authors | 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 |
| 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 number | RP95852 |
| Journal | eLife |
| Journal citation | 13 |
| ISSN | 2050-084X |
| Year | 2024 |
| Publisher | eLife 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 ID | 39480699 |
| Web address (URL) | https://doi.org/10.7554/eLife.95852 |
| Publication dates | |
| Published | 31 Oct 2024 |