ArticleThe Journal of biological chemistry2010
Structural basis for the cAMP-dependent gating in the human HCN4 channel.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 88 citations in OpenAlex.
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- 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
- A high affinity switch for cAMP in the HCN pacemaker channels.Nature communications · 2024Article
- 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
- Propofol, an Anesthetic Agent, Inhibits HCN Channels through the Allosteric Modulation of the cAMP-Dependent Gating Mechanism.Biomolecules · 2022Article
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Uncoupling of Voltage- and Ligand-Induced Activation in HCN2 Channels by Glycine Inserts.Frontiers in physiology · 2022Article
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- 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
- cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4.Frontiers in physiology · 2020Review
- Identification of undecylenic acid as EAG channel inhibitor using surface plasmon resonance-based screen of KCNH channels.BMC pharmacology & toxicology · 2019Article
- Novel Fluorescent Cyclic Nucleotide Derivatives to Study CNG and HCN Channel Function.Biophysical journal · 2019Article
- Identification and characterization of a series of novel HCN channel inhibitors.Acta pharmacologica Sinica · 2019Article
- cAMP binds to closed, inactivated, and open sea urchin HCN channels in a state-dependent manner.The Journal of general physiology · 2019Article
- Hydrophobic alkyl chains substituted to the 8-position of cyclic nucleotides enhance activation of CNG and HCN channels by an intricate enthalpy - entropy compensation.Scientific reports · 2018Article
- Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels by β-blocker carvedilol.British journal of pharmacology · 2018Article
- All four subunits of HCN2 channels contribute to the activation gating in an additive but intricate manner.The Journal of general physiology · 2018Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperpolarization-activated cAMP-regulated (HCN) channels play important physiological roles in both cardiovascular and central nervous systems. Among the four HCN isoforms, HCN2 and HCN4 show high expression levels in the human heart, with HCN4 being the major cardiac isoform. The previously published crystal structure of the mouse HCN2 (mHCN2) C-terminal fragment, including the C-linker and the cyclic-nucleotide binding domain (CNBD), has provided many insights into cAMP-dependent gating in HCN channels. However, structures of other mammalian HCN channel isoforms have been lacking. Here we used a combination of approaches including structural biology, biochemistry, and electrophysiology to study cAMP-dependent gating in HCN4 channel. First we solved the crystal structure of the C-terminal fragment of human HCN4 (hHCN4) channel at 2.4 Å. Overall we observed a high similarity between mHCN2 and hHCN4 crystal structures. Functional comparison between two isoforms revealed that compared with mHCN2, the hHCN4 protein exhibited marked different contributions to channel function, such as a ∼3-fold reduction in the response to cAMP. Guided by structural differences in the loop region between β4 and β5 strands, we identified residues that could partially account for the differences in response to cAMP between mHCN2 and hHCN4 proteins. Moreover, upon cAMP binding, the hHCN4 C-terminal protein exerts a much prolonged effect in channel deactivation that could have significant physiological contributions.
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