ArticleProceedings of the National Academy of Sciences of the United States of America2019
Bipolar switching by HCN voltage sensor underlies hyperpolarization activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- Towards a unified gating scheme for the CNBD ion channel family.The Journal of general 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
- An Allosteric Model for Electromechanical Coupling in Cardiac CNBD Channels.bioRxiv : the preprint server for biology · 2025Article
- Hippocampal dorsal CA1: Functional connectivity and role in HCN channelopathies in affective diseases and epilepsy.IBRO neuroscience reports · 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
- Mapping the contribution of the C-linker domain to gating polarity in CNBD channels.Biophysical journal · 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
- Similar voltage-sensor movement in spHCN channels can cause closing, opening, or inactivation.The Journal of general physiology · 2023Article
- A gating lever and molecular logic gate that couple voltage and calcium sensor activation to opening in BK potassium channels.Science advances · 2022Article
- Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels.Communications biology · 2022Article
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- IProgress in biophysics and molecular biology · 2021Review
- A second S4 movement opens hyperpolarization-activated HCN channels.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mapping Electromechanical Coupling Pathways in Voltage-Gated Ion Channels: Challenges and the Way Forward.Journal of molecular biology · 2021Review
- Electromechanical coupling mechanism for activation and inactivation of an HCN channel.Nature communications · 2021Article
- Mapping temperature-dependent conformational change in the voltage-sensing domain of an engineered heat-activated KProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Allosteric signaling in C-linker and cyclic nucleotide-binding domain of HCN2 channels.Biophysical journal · 2021Article
- Review
- 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
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Despite sharing a common architecture with archetypal voltage-gated ion channels (VGICs), hyperpolarization- and cAMP-activated ion (HCN) channels open upon hyperpolarization rather than depolarization. The basic motions of the voltage sensor and pore gates are conserved, implying that these domains are inversely coupled in HCN channels. Using structure-guided protein engineering, we systematically assembled an array of mosaic channels that display the full complement of voltage-activation phenotypes observed in the VGIC superfamily. Our studies reveal that the voltage sensor of the HCN channel has an intrinsic ability to drive pore opening in either direction and that the extra length of the HCN S4 is not the primary determinant for hyperpolarization activation. Tight interactions at the HCN voltage sensor-pore interface drive the channel into an hERG-like inactivated state, thereby obscuring its opening upon depolarization. This structural element in synergy with the HCN cyclic nucleotide-binding domain and specific interactions near the pore gate biases the channel toward hyperpolarization-dependent opening. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily and identify the essential determinants of gating polarity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.