ArticleThe Journal of general physiology2023
Alkali metal cations modulate the geometry of different binding sites in HCN4 selectivity filter for permeation or block.
Article in The Journal of general physiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 11 citations in OpenAlex.
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- Selectivity Filter Dynamics Define Ion Conductance and Selectivity Differences in CNG and HCN Channels.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Atomistic mechanism of non-selective cation permeation in cyclic nucleotide-gated CNGA1 ion channel by molecular dynamics simulations.Communications biology · 2025Article
- Atomistic mechanisms of calcium permeation modulated by Q/R editing and selectivity filter mutations in GluA2 AMPA receptors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- 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
- Structural Insights Into the Opening Mechanism of C1C2 Channelrhodopsin.Journal of the American Chemical Society · 2025Article
- Structural determinants of ivabradine block of the open pore of HCN4.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural basis for hyperpolarization-dependent opening of human HCN1 channel.Nature communications · 2024Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperpolarization-activated cyclic-nucleotide gated (HCN) channels are important for timing biological processes like heartbeat and neuronal firing. Their weak cation selectivity is determined by a filter domain with only two binding sites for K+ and one for Na+. The latter acts as a weak blocker, which is released in combination with a dynamic widening of the filter by K+ ions, giving rise to a mixed K+/Na+ current. Here, we apply molecular dynamics simulations to systematically investigate the interactions of five alkali metal cations with the filter of the open HCN4 pore. Simulations recapitulate experimental data like a low Li+ permeability, considerable Rb+ conductance, a block by Cs+ as well as a punch through of Cs+ ions at high negative voltages. Differential binding of the cation species in specific filter sites is associated with structural adaptations of filter residues. This gives rise to ion coordination by a cation-characteristic number of oxygen atoms from the filter backbone and solvent. This ion/protein interplay prevents Li+, but not Na+, from entry into and further passage through the filter. The site equivalent to S3 in K+ channels emerges as a preferential binding and presumably blocking site for Cs+. Collectively, the data suggest that the weak cation selectivity of HCN channels and their block by Cs+ are determined by restrained cation-generated rearrangements of flexible filter residues.
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