ArticleThe Journal of biological chemistry2014
A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 79 citations in OpenAlex.
- 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
- An inter-subunit path is required for entropically-driven and negatively cooperative binding of cyclic nucleotides in the HCN2 channel.Communications biology · 2026Article
- Drug resistance and tumor heterogeneity: cells and ensembles.Biophysical reviews · 2025Review
- 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
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- Conformational changes in protein kinase A along its activation cycle are rooted in the folding energetics of cyclic-nucleotide binding domains.The Journal of biological chemistry · 2023Article
- A Novel Flow Cytometry-Based Assay for the Identification of HCN4 CNBD Ligands.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels.Communications biology · 2022Article
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Blockage of HCN Channels Inhibits the Function of P2X Receptors in Rat Dorsal Root Ganglion Neurons.Neurochemical research · 2022Article
- Gating movements and ion permeation in HCN4 pacemaker channels.Molecular cell · 2021Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Rational design of a mutation to investigate the role of the brain protein TRIP8b in limiting the cAMP response of HCN channels in neurons.The Journal of general physiology · 2020Article
- Allosteric conformational change of a cyclic nucleotide-gated ion channel revealed by DEER spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.The Journal of membrane biology · 2020Article
- cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4.Frontiers in physiology · 2020Review
- Review
- Binding and structural asymmetry governs ligand sensitivity in a cyclic nucleotide-gated ion channel.The Journal of general physiology · 2019Article
- Activation of PKA via asymmetric allosteric coupling of structurally conserved cyclic nucleotide binding domains.Nature communications · 2019Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels control neuronal and cardiac electrical rhythmicity. There are four homologous isoforms (HCN1-4) sharing a common multidomain architecture that includes an N-terminal transmembrane tetrameric ion channel followed by a cytoplasmic "C-linker," which connects a more distal cAMP-binding domain (CBD) to the inner pore. Channel opening is primarily stimulated by transmembrane elements that sense membrane hyperpolarization, although cAMP reduces the voltage required for HCN activation by promoting tetramerization of the intracellular C-linker, which in turn relieves auto-inhibition of the inner pore gate. Although binding of cAMP has been proposed to relieve auto-inhibition by affecting the structure of the C-linker and CBD, the nature and extent of these cAMP-dependent changes remain limitedly explored. Here, we used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo-CBD of HCN4. Our data indicate that the CBD exists in a dynamic two-state equilibrium, whose position as gauged by NMR chemical shifts correlates with the V½ voltage measured through electrophysiology. In the absence of cAMP, the most populated CBD state leads to steric clashes with the activated or "tetrameric" C-linker, which becomes energetically unfavored. The steric clashes of the apo tetramer are eliminated either by cAMP binding, which selects for a CBD state devoid of steric clashes with the tetrameric C-linker and facilitates channel opening, or by a transition of apo-HCN to monomers or dimer of dimers, in which the C-linker becomes less structured, and channel opening is not facilitated.
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