ArticleeLife2019
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- Extracellular salt bridge networks around S4 implicated in HCN channel gating and heart disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity.Science advances · 2025Article
- Different fluorescent labels report distinct components of spHCN channel voltage sensor movement.The Journal of general physiology · 2024Article
- Article
- Mapping the contribution of the C-linker domain to gating polarity in CNBD channels.Biophysical journal · 2024Article
- Structural basis for hyperpolarization-dependent opening of human HCN1 channel.Nature communications · 2024Article
- An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.BMC biology · 2024Article
- Article
- Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization.Nature communications · 2023Article
- Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel.bioRxiv : the preprint server for biology · 2023Article
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels.eLife · 2023Article
- Molecular dynamics study of ClCellular and molecular life sciences : CMLS · 2023Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel.Nature communications · 2022Article
- Mechanism of voltage gating in the voltage-sensing phosphatase Ci-VSP.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mechanism of voltage sensing in CaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels.Communications biology · 2022Article
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Authors and funding
7 authors.
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Abstract
In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltage-sensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (~20 μs) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.
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