ArticleThe Journal of biological chemistry2011
Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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85 citing papers in PubMed, 127 citations in OpenAlex.
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- Lipid bilayers determine allostery but not intrinsic affinity of cAMP to pacemaker channels.Nature communications · 2026Article
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- Structural determinants of voltage sensitivity in hyperpolarization-activated ion channels and their persistence in the evolutionary scale.Pflugers Archiv : European journal of physiology · 2026Article
- Predicting Binding Affinities for the Binding Domain of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Isoforms Using Free-Energy Perturbation.bioRxiv : the preprint server for biology · 2026Article
- Towards a unified gating scheme for the CNBD ion channel family.The Journal of general physiology · 2026Review
- A Novel Loss of Function Variant inMolecular syndromology · 2025Article
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- Ligand-Coupled Conformational Changes in a Cyclic Nucleotide-Gated Ion Channel Revealed by Time-Resolved Transition Metal Ion FRET.bioRxiv : the preprint server for biology · 2024Article
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- A high affinity switch for cAMP in the HCN pacemaker channels.Nature communications · 2024Article
- Article
- Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel.bioRxiv : the preprint server for biology · 2023Article
- Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel.Nature communications · 2023Article
- A Novel Flow Cytometry-Based Assay for the Identification of HCN4 CNBD Ligands.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.Nature structural & molecular biology · 2023Article
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Validation of the binding stoichiometry between HCN channels and their neuronal regulator TRIP8b by single molecule measurements.Frontiers in physiology · 2022Article
- Uncoupling of Voltage- and Ligand-Induced Activation in HCN2 Channels by Glycine Inserts.Frontiers in physiology · 2022Article
- Gating movements and ion permeation in HCN4 pacemaker channels.Molecular cell · 2021Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels.
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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.