ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
- Membrane-forming phospholipids allosterically modulate native-state prolyl isomerization in a CNG channel.Protein science : a publication of the Protein Society · 2025Article
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- 5-Hydroxytryptamine Enhances the Pacemaker Activity of Interstitial Cells of Cajal in Mouse Colon.International journal of molecular sciences · 2024Article
- Anionic lipids unlock the gates of select ion channels in the pacemaker family.Nature structural & molecular biology · 2022Article
- Endocannabinoids Tune Intrinsic Excitability in O-LM Interneurons by Direct Modulation of Postsynaptic Kv7 Channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- HCN Channels: New Therapeutic Targets for Pain Treatment.Molecules (Basel, Switzerland) · 2018Review
- Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels.Frontiers in physiology · 2017Review
- HCN Channels Modulators: The Need for Selectivity.Current topics in medicinal chemistry · 2016Review
- Protein kinase C bidirectionally modulates Ih and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons.The Journal of physiology · 2015Article
- Extracellular pH regulates excitability of vomeronasal sensory neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Protein kinase C activation mediates interferon-β-induced neuronal excitability changes in neocortical pyramidal neurons.Journal of neuroinflammation · 2014Article
- General anesthesia mediated by effects on ion channels.World journal of critical care medicine · 2012Review
- Article
- Exploring HCN channels as novel drug targets.Nature reviews. Drug discovery · 2011Review
- PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Article
- Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010Article
- Dendritic HCN channels shape excitatory postsynaptic potentials at the inner hair cell afferent synapse in the mammalian cochlea.Journal of neurophysiology · 2010Article
- IH current generates the afterhyperpolarisation following activation of subthreshold cortical synaptic inputs to striatal cholinergic interneurons.The Journal of physiology · 2009Article
- Rescue of a trafficking defective human pacemaker channel via a novel mechanism: roles of Src, Fyn, and Yes tyrosine kinases.The Journal of biological chemistry · 2009Article
- Voltage-dependent opening of HCN channels: Facilitation or inhibition by the phytoestrogen, genistein, is determined by the activation status of the cyclic nucleotide gating ring.Biochimica et biophysica acta · 2009Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hyperpolarization-activated pacemaker currents (I(H)) contribute to the subthreshold properties of excitable cells and thereby influence behaviors such as synaptic integration and the appearance and frequency of intrinsic rhythmic activity. Accordingly, modulation of I(H) contributes to cellular plasticity. Although I(H) activation is regulated by a plethora of neurotransmitters, including some that act via phospholipase C (PLC), the only second messengers known to alter I(H) voltage dependence are cAMP, internal protons (H+(I)s), and phosphatidylinositol-4,5-phosphate. Here, we show that 4beta-phorbol-12-myristate-13-acetate (4betaPMA), a stereoselective C-1 diacylglycerol-binding site agonist, enhances voltage-dependent opening of wild-type and cAMP/H+(I)-uncoupled hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channels, but does not alter gating of the plant hyperpolarization-activated channel, KAT1. Pharmacological analysis indicates that 4betaPMA exerts its effects on HCN gating via sequential activation of PKC and diacylglycerol kinase (DGK) coupled with upregulation of MAPK (mitogen-activated protein kinase) and phospholipase A2 (PLA2), but its action is independent of phosphoinositide kinase 3 (PI3K) and PI4K. Demonstration that both phosphatidic acid and arachidonic acid (AA) directly facilitate HCN gating suggests that these metabolites may serve as the messengers downstream of DGK and PLA2, respectively. 4BetaPMA-mediated suppression of the maximal HCN current likely arises from channel interaction with AA coupled with an enhanced membrane retrieval triggered by the same pathways that modulate channel gating. These results indicate that regulation of excitable cell behavior by neurotransmitter-mediated modulation of I(H) may be exerted via changes in three signaling lipids in addition to the allosteric actions of cAMP and H+(I)s.
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Registered trials
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.