ArticleThe Journal of general physiology2006
Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2.
Article in The Journal of general physiology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers, 1 of them a synthesis that pooled it.
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Who cites it
100 citing papers in PubMed, 1 synthesis or guideline pooled it, 162 citations in OpenAlex.
- The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review.Frontiers in molecular neuroscience · 2022Pooled it
- The voltage dependence of I(h) in human myelinated axons.The Journal of physiology · 2012Trial
- PIP2 binding at allosteric site blocks activation in human rod CNG channels.Nature communications · 2026Article
- Lipid bilayers determine allostery but not intrinsic affinity of cAMP to pacemaker channels.Nature communications · 2026Article
- Distinct Modulation ofeNeuro · 2024Article
- PIP2 inhibits pore opening of the cyclic nucleotide-gated channel SthK.Nature communications · 2024Article
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- PI4KIIIβ-Mediated Phosphoinositides Metabolism Regulates Function of the VTA Dopaminergic Neurons and Depression-Like Behavior.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Anionic lipids unlock the gates of select ion channels in the pacemaker family.Nature structural & molecular biology · 2022Article
- HCN2 Ion Channels Drive Pain in Rodent Models of Migraine.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism.The Journal of general physiology · 2022Article
- Spotlight on the Binding Affinity of Ion Channels for Phosphoinositides: From the Study of Sperm Flagellum.Frontiers in physiology · 2022Review
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- Computational Prediction of Phosphoinositide Binding to Hyperpolarization-Activated Cyclic-Nucleotide Gated Channels.Frontiers in physiology · 2022Article
- Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- The retrotrapezoid nucleus and the neuromodulation of breathing.Journal of neurophysiology · 2021Review
- 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
- A PIPCommunications biology · 2020Article
- Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.The Journal of membrane biology · 2020Article
40 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The voltage dependence of activation of the HCN hyperpolarization-activated cation channels is shifted in inside-out patches by -40 to -60 mV relative to activation in intact cells, a phenomenon referred to as rundown. Less than 20 mV of this hyperpolarizing shift can be due to the influence of the canonical modulator of HCN channels, cAMP. Here we study the role of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in HCN channel rundown, as hydrolysis of PI(4,5)P(2) by lipid phosphatases is thought to underlie rundown of several other channels. We find that bath application of exogenous PI(4,5)P(2) reverses the effect of rundown, producing a large depolarizing shift in HCN2 activation. A synthetic short chain analogue of PI(4,5)P(2), dioctanoyl phosphatidylinositol 4,5-bisphosphate, shifts the HCN2 activation curve to more positive potentials in a dose-dependent manner. Other dioctanoyl phosphatidylinositides with one or more phosphates on the lipid headgroup also shift activation, although phosphatidylinositol (PI) is ineffective. Several lines of evidence suggest that HCN2 is also regulated by endogenous PI(4,5)P(2): (a) blockade of phosphatases slows the hyperpolarizing shift upon patch excision; (b) application of an antibody that binds and depletes membrane PIP(2) causes a further hyperpolarizing shift in activation; (c) the shift in activation upon patch excision can be partially reversed by MgATP; and (d) the effect of MgATP is blocked by wortmannin, an inhibitor of PI kinases. Finally, recordings from rabbit sinoatrial cells demonstrate that diC(8) PI(4,5)P(2) delays the rundown of native HCN currents. Thus, both native and recombinant HCN channels are regulated by PI(4,5)P(2).
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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.