ArticleAmerican journal of physiology. Cell physiology2008
Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels.
Article in American journal of physiology. Cell physiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- HCN1 is a primary HCN Pacemaker Channel in Neurons.Nature communications · 2026Article
- Magnesium Ions as Modulators of Voltage-Gated and Ligand-Gated Ion Channels in Central Neurons.International journal of molecular sciences · 2025Review
- Subunit-specific conductance of single homomeric and heteromeric HCN pacemaker channels at femtosiemens resolution.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Effects of Axonal Demyelination, Inflammatory Cytokines and Divalent Cation Chelators on Thalamic HCN Channels and Oscillatory Bursting.International journal of molecular sciences · 2022Article
- Article
- Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission.Neuroscience and biobehavioral reviews · 2016Review
- Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels.Biological psychiatry · 2015Article
- An N-terminal deletion variant of HCN1 in the epileptic WAG/Rij strain modulates HCN current densities.Frontiers in molecular neuroscience · 2015Article
- cAMP control of HCN2 channel Mg2+ block reveals loose coupling between the cyclic nucleotide-gating ring and the pore.PloS one · 2014Article
- Inner activation gate in S6 contributes to the state-dependent binding of cAMP in full-length HCN2 channel.The Journal of general physiology · 2012Article
- Effects of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers on the proliferation and cell cycle progression of embryonic stem cells.Pflugers Archiv : European journal of physiology · 2011Article
- Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat.Clinical and experimental pharmacology & physiology · 2010Article
- 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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3 authors at 1 institution in 1 country.
Funding
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarization that creates time-dependent, inward rectifying currents, gated by the movement of the intrinsic voltage sensor S4. However, inward rectification of the HCN currents is not only observed in the time-dependent HCN currents, but also in the instantaneous HCN tail currents. Inward rectification can also be seen in mutant HCN channels that have mainly time-independent currents (5). In the present study, we show that intracellular Mg(2+) functions as a voltage-dependent blocker of HCN channels, acting to reduce the outward currents. The affinity of HCN channels for Mg(2+) is in the physiological range, with Mg(2+) binding with an IC(50) of 0.53 mM in HCN2 channels and 0.82 mM in HCN1 channels at +50 mV. The effective electrical distance for the Mg(2+) binding site was found to be 0.19 for HCN1 channels, suggesting that the binding site is in the pore. Removing a cysteine in the selectivity filter of HCN1 channels reduced the affinity for Mg(2+), suggesting that this residue forms part of the binding site deep within the pore. Our results suggest that Mg(2+) acts as a voltage-dependent pore blocker and, therefore, reduces outward currents through HCN channels. The pore-blocking action of Mg(2+) may play an important physiological role, especially for the slowly gating HCN2 and HCN4 channels. Mg(2+) could potentially block outward hyperpolarizing HCN currents at the plateau of action potentials, thus preventing a premature termination of the action potential.
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