Lipid regulation of hERG1 channel function

Williams E. Miranda, Jiqing Guo, Haydee Mesa-Galloso, Valentina Corradi, James P. Lees-Miller, D. Peter Tieleman (), Henry J. Duff () and Sergei Yu. Noskov ()
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Williams E. Miranda: University of Calgary
Jiqing Guo: University of Calgary
Haydee Mesa-Galloso: University of Calgary
Valentina Corradi: University of Calgary
James P. Lees-Miller: University of Calgary
D. Peter Tieleman: University of Calgary
Henry J. Duff: University of Calgary
Sergei Yu. Noskov: University of Calgary

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21681-8

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DOI: 10.1038/s41467-021-21681-8

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