Lipid regulation of hERG1 channel function
Open Access
- 3 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-10
- https://doi.org/10.1038/s41467-021-21681-8
Abstract
The lipid regulation of mammalian ion channel function has emerged as a fundamental mechanism in the control of electrical signalling and transport specificity in various cell types. In this work, we combine molecular dynamics simulations, mutagenesis, and electrophysiology to provide mechanistic insights into how lipophilic molecules (ceramide-sphingolipid probe) alter gating kinetics and K+ currents of hERG1. We show that the sphingolipid probe induced a significant left shift of activation voltage, faster deactivation rates, and current blockade comparable to traditional hERG1 blockers. Microseconds-long MD simulations followed by experimental mutagenesis elucidated ceramide specific binding locations at the interface between the pore and voltage sensing domains. This region constitutes a unique crevice present in mammalian channels with a non-swapped topology. The combined experimental and simulation data provide evidence for ceramide-induced allosteric modulation of the channel by a conformational selection mechanism.This publication has 54 references indexed in Scilit:
- Ceramide modulates HERG potassium channel gating by translocation into lipid raftsAmerican Journal of Physiology-Cell Physiology, 2010
- Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid TypesThe Journal of Physical Chemistry B, 2010
- Conformational selection or induced fit: A flux description of reaction mechanismProceedings of the National Academy of Sciences of the United States of America, 2009
- GridMAT‐MD: A grid‐based membrane analysis tool for use with molecular dynamicsJournal of Computational Chemistry, 2008
- Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosisCardiovascular Research, 2007
- Canonical sampling through velocity rescalingThe Journal of Chemical Physics, 2007
- Exaggerated block of hERG (KCNH2) and prolongation of action potential duration by erythromycin at temperatures between 37°C and 42°CHeart Rhythm, 2005
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- Molecular dynamics with coupling to an external bathThe Journal of Chemical Physics, 1984
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983