ArticleThe Journal of biological chemistry2012
Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Glial Ion Channels in Myelin Pathophysiology: Insights from Leukodystrophies.Life (Basel, Switzerland) · 2025Review
- Identification of cCMP- and cUMP-binding proteins using cCMP and cUMP coupled to agarose and biotin matrices.PloS one · 2025Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.eLife · 2024Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.bioRxiv : the preprint server for biology · 2024Article
- Modulating cyclic nucleotides pathways by bioactive compounds in combatting anxiety and depression disorders.Molecular biology reports · 2023Review
- Photoreceptor Ion Channels in Signaling and Disease.Advances in experimental medicine and biology · 2023Article
- Putative Nucleotide-Based Second Messengers in the Archaeal Model OrganismsFrontiers in microbiology · 2021Article
- Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels.Frontiers in molecular neuroscience · 2021Review
- Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Binding and structural asymmetry governs ligand sensitivity in a cyclic nucleotide-gated ion channel.The Journal of general physiology · 2019Article
- Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode.Naunyn-Schmiedeberg's archives of pharmacology · 2019Article
- TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome.The Journal of physiology · 2018Article
- cUMP hydrolysis by PDE3B.Naunyn-Schmiedeberg's archives of pharmacology · 2018Article
- Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides.Frontiers in cellular neuroscience · 2018Article
- Hippocampal Characteristics and Invariant Sequence Elements Distribution of GLRA2 and GLRA3 C-to-U Editing.Molecular syndromology · 2017Article
- Association between hyperpolarization-activated channel in interstitial cells of Cajal and gastrointestinal dysmotility induced by malignant ascites.Oncology letters · 2017Article
- cUMP hydrolysis by PDE3A.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- HCN Channels Modulators: The Need for Selectivity.Current topics in medicinal chemistry · 2016Review
- Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides.The Journal of biological chemistry · 2016Article
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9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated in vivo by direct binding of the second messenger cAMP. This process plays a fundamental role in the fine-tuning of HCN channel activity and is critical for the modulation of cardiac and neuronal rhythmicity. Here, we identify the pyrimidine cyclic nucleotide cCMP as another regulator of HCN channels. We demonstrate that cCMP shifts the activation curves of two members of the HCN channel family, HCN2 and HCN4, to more depolarized voltages. Moreover, cCMP speeds up activation and slows down deactivation kinetics of these channels. The two other members of the HCN channel family, HCN1 and HCN3, are not sensitive to cCMP. The modulatory effect of cCMP is reversible and requires the presence of a functional cyclic nucleotide-binding domain. We determined an EC(50) value of ∼30 μm for cCMP compared with 1 μm for cAMP. Notably, cCMP is a partial agonist of HCN channels, displaying an efficacy of ∼0.6. cCMP increases the frequency of pacemaker potentials from isolated sinoatrial pacemaker cells in the presence of endogenous cAMP concentrations. Electrophysiological recordings indicated that this increase is caused by a depolarizing shift in the activation curve of the native HCN current, which in turn leads to an enhancement of the slope of the diastolic depolarization of sinoatrial node cells. In conclusion, our findings establish cCMP as a gating regulator of HCN channels and indicate that this cyclic nucleotide has to be considered in HCN channel-regulated processes.
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