Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues

Voltage-gated potassium (K V ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability,...

Full description

Saved in:
Bibliographic Details
Published in:eLife 2023-06, Vol.12
Main Authors: Bohannon, Briana M, Jowais, Jessica J, Nyberg, Leif, Olivier-Meo, Vanessa, Corradi, Valentina, Tieleman, D Peter, Liin, Sara I, Larsson, H Peter
Format: Article
Language:English
Subjects:
Action potential
Channel gating
Epilepsy
Excitability
Fatty acids
Heart
Hydrogen bonding
Long QT syndrome
Mutation
Polyunsaturated fatty acids
Potassium
potassium channel
Potassium channels (voltage-gated)
Recovery of function
Structural Biology and Molecular Biophysics
Tyrosine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Voltage-gated potassium (K V ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K V channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I Ks channel – a tetrameric potassium channel complex formed by K V 7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I Ks channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I Ks channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I Ks channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.85773