ArticleProceedings of the National Academy of Sciences of the United States of America2001
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed.
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- HCN1 is a primary HCN Pacemaker Channel in Neurons.Nature communications · 2026Article
- 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
- A Novel Loss of Function Variant inMolecular syndromology · 2025Article
- Combination of Autodisplay and Dynamic Pharmacophore Modeling Reveals New Insights into Cyclic Nucleotide Binding in Hyperpolarization-Activated and Cyclic Nucleotide-Gated Ion Channel 4 (HCN4).ACS pharmacology & translational science · 2024Article
- 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
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- Loose Coupling between the Voltage Sensor and the Activation Gate in Mammalian HCN Channels Suggests a Gating Mechanism.International journal of molecular sciences · 2024Article
- Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel.bioRxiv : the preprint server for biology · 2023Article
- Molecular Dynamics Simulations of the Cardiac Ryanodine Receptor Type 2 (RyR2) Gating Mechanism.The journal of physical chemistry. B · 2022Article
- Gating movements and ion permeation in HCN4 pacemaker channels.Molecular cell · 2021Article
- Cryo-EM structure of the hyperpolarization-activated inwardly rectifying potassium channel KAT1 from Arabidopsis.Cell research · 2020Article
- Diversity of voltage-gated potassium channels and cyclic nucleotide-binding domain-containing channels in eukaryotes.Scientific reports · 2020Article
- The HCN domain is required for HCN channel cell-surface expression and couples voltage- and cAMP-dependent gating mechanisms.The Journal of biological chemistry · 2020Article
- Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.The Journal of membrane biology · 2020Article
- Article
- All four subunits of HCN2 channels contribute to the activation gating in an additive but intricate manner.The Journal of general physiology · 2018Article
- Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker KNature structural & molecular biology · 2018Article
- Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening.Nature communications · 2017Article
22 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
Voltage-gated channels are normally opened by depolarization and closed by repolarization of the membrane. Despite sharing significant sequence homology with voltage-gated K(+) channels, the gating of hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels has the opposite dependence on membrane potential: hyperpolarization opens, whereas depolarization closes, these channels. The mechanism and structural basis of the process that couples voltage sensor movement to HCN channel opening and closing is not understood. On the basis of our previous studies of a mutant HERG (human ether-a-go-go-related gene) channel, we hypothesized that the intracellular linker that connects the fourth and fifth transmembrane domains (S4-S5 linker) of HCN channels might be important for channel gating. Here, we used alanine-scanning mutagenesis of the HCN2 S4-S5 linker to identify three residues, E324, Y331, and R339, that when mutated disrupted normal channel closing. Mutation of a basic residue in the S4 domain (R318Q) prevented channel opening, presumably by disrupting S4 movement. However, channels with R318Q and Y331S mutations were constitutively open, suggesting that these channels can open without a functioning S4 domain. We conclude that the S4-S5 linker mediates coupling between voltage sensing and HCN channel activation. Our findings also suggest that opening of HCN and related channels corresponds to activation of a gate located near the inner pore, rather than recovery of channels from a C-type inactivated state.
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