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Lipid regulation of hERG1 channel function.

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.

SUBMITTER: Miranda WE

PROVIDER: S-EPMC7930123 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Lipid regulation of hERG1 channel function.

Miranda Williams E WE Guo Jiqing J Mesa-Galloso Haydee H Corradi Valentina V Lees-Miller James P JP Tieleman D Peter DP Duff Henry J HJ Noskov Sergei Yu SY

Nature communications 20210303 1

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<sup>+</sup> currents of hERG1. We show that the sphingolipid probe induced a significant left shift of ac ...[more]

PMID: 33658490

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Project description:Membrane protein function is regulated by the lipid bilayer composition. In many cases the changes in function correlate with changes in the lipid intrinsic curvature (c 0), and c 0 is considered a determinant of protein function. Yet, water-soluble amphiphiles that cause either negative or positive changes in curvature have similar effects on membrane protein function, showing that changes in lipid bilayer properties other than c 0 are important-and may be dominant. To further investigate the mechanisms underlying the bilayer regulation of protein function, we examined how maneuvers that alter phospholipid head groups effective "size"-and thereby c 0-alter gramicidin (gA) channel function. Using dioleoylphospholipids and planar bilayers, we varied the head groups' physical volume and the electrostatic repulsion among head groups (and thus their effective size). When 1,2-dioleyol-sn-glycero-3-phosphocholine (DOPC), was replaced by 1,2-dioleyol-sn-glycero-3-phosphoethanolamine (DOPE) with a smaller head group (causing a more negative c 0), the channel lifetime (τ) is decreased. When the pH of the solution bathing a 1,2-dioleyol-sn-glycero-3-phosphoserine (DOPS) bilayer is decreased from 7 to 3 (causing decreased head group repulsion and a more negative c 0), τ is decreased. When some DOPS head groups are replaced by zwitterionic head groups, τ is similarly decreased. These effects do not depend on the sign of the change in surface charge. In DOPE:DOPC (3:1) bilayers, pH changes from 5→9 to 5→0 (both increasing head group electrostatic repulsion, thereby causing a less negative c 0) both increase τ. Nor do the effects depend on the use of planar, hydrocarbon-containing bilayers, as similar changes were observed in hydrocarbon-free lipid vesicles. Altering the interactions among phospholipid head groups may alter also other bilayer properties such as thickness or elastic moduli. Such changes could be excluded using capacitance measurements and single channel measurements on gA channels of different lengths. We conclude that changes gA channel function caused by changes in head group effective size can be predicted from the expected changes in c 0.

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Lipid regulation of hERG1 channel function.

Publications

Lipid regulation of hERG1 channel function.

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