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Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization

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  • Lucas J. Handlin

    (Saint Louis University School of Medicine)

  • Gucan Dai

    (Saint Louis University School of Medicine)

Abstract

Ion channels function within a membrane environment characterized by dynamic lipid compartmentalization. Limited knowledge exists regarding the response of voltage-gated ion channels to transmembrane potential within distinct membrane compartments. By leveraging fluorescence lifetime imaging microscopy (FLIM) and Förster resonance energy transfer (FRET), we visualized the localization of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in membrane domains. HCN4 exhibits a greater propensity for incorporation into ordered lipid domains compared to HCN1. To investigate the conformational changes of the S4 helix voltage sensor of HCN channels, we used dual stop-codon suppression to incorporate different noncanonical amino acids, orthogonal click chemistry for site-specific fluorescence labeling, and transition metal FLIM-FRET. Remarkably, altered FRET levels were observed between VSD sites within HCN channels upon disruption of membrane domains. We propose that the voltage-sensor rearrangements, directly influenced by membrane lipid domains, can explain the heightened activity of pacemaker HCN channels when localized in cholesterol-poor, disordered lipid domains, leading to membrane hyperexcitability and diseases.

Suggested Citation

  • Lucas J. Handlin & Gucan Dai, 2023. "Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42363-7
    DOI: 10.1038/s41467-023-42363-7
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    References listed on IDEAS

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    1. Christian Eggeling & Christian Ringemann & Rebecca Medda & Günter Schwarzmann & Konrad Sandhoff & Svetlana Polyakova & Vladimir N. Belov & Birka Hein & Claas von Middendorff & Andreas Schönle & Stefan, 2009. "Direct observation of the nanoscale dynamics of membrane lipids in a living cell," Nature, Nature, vol. 457(7233), pages 1159-1162, February.
    2. Rosamary Ramentol & Marta E. Perez & H. Peter Larsson, 2020. "Gating mechanism of hyperpolarization-activated HCN pacemaker channels," Nature Communications, Nature, vol. 11(1), pages 1-7, December.
    3. Gucan Dai & Teresa K. Aman & Frank DiMaio & William N. Zagotta, 2021. "Electromechanical coupling mechanism for activation and inactivation of an HCN channel," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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    Cited by:

    1. Lucas J. Handlin & Natalie L. Macchi & Nicolas L. A. Dumaire & Lyuba Salih & Erin N. Lessie & Kyle S. McCommis & Aubin Moutal & Gucan Dai, 2024. "Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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