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Gating movements and ion permeation in HCN4 pacemaker channels.
<div class='caption-title'>HCN4 structure and its comparison with that of HCN1</div>
<div class='caption-title'>Structural, biochemical, and functional evidence for the tetrad, connecting the transmembrane and cytosolic domains in HCN4</div>
Saponaro A, Bauer D, Giese MH, Swuec P, Porro A, Gasparri F, Sharifzadeh AS, Chaves-Sanjuan A, Alberio L, Parisi G, Cerutti G, Clarke OB, Hamacher K, Colecraft HM, Mancia F, Hendrickson WA, Siegelbaum SA, DiFrancesco D, Bolognesi M, Thiel G, Santoro B, Moroni A
OpenAccess logo Mol Cell 81 2929-2943.e6 (2021)
Related entries: 7nmn, 7np4

Cited: 32 times
EuropePMC logo PMID: 34166608

Abstract

The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures sheds light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlights the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation. Our results contribute mechanistic understanding on HCN channel gating, cyclic nucleotide-dependent modulation, and ion permeation.

Articles - 7np3 mentioned but not cited (8)

  1. Gating movements and ion permeation in HCN4 pacemaker channels. Saponaro A, Bauer D, Giese MH, Swuec P, Porro A, Gasparri F, Sharifzadeh AS, Chaves-Sanjuan A, Alberio L, Parisi G, Cerutti G, Clarke OB, Hamacher K, Colecraft HM, Mancia F, Hendrickson WA, Siegelbaum SA, DiFrancesco D, Bolognesi M, Thiel G, Santoro B, Moroni A. Mol Cell 81 2929-2943.e6 (2021)
  2. Interplay between VSD, pore, and membrane lipids in electromechanical coupling in HCN channels. Elbahnsi A, Cowgill J, Burtscher V, Wedemann L, Zeckey L, Chanda B, Delemotte L. Elife 12 e80303 (2023)
  3. Similar voltage-sensor movement in spHCN channels can cause closing, opening, or inactivation. Wu X, Cunningham KP, Ramentol R, Perez ME, Larsson HP. J Gen Physiol 155 e202213170 (2023)
  4. Weak Cation Selectivity in HCN Channels Results From K+-Mediated Release of Na+ From Selectivity Filter Binding Sites. Bauer D, Wissmann J, Moroni A, Thiel G, Hamacher K. Function (Oxf) 3 zqac019 (2022)
  5. Structures of a sperm-specific solute carrier gated by voltage and cAMP. Kalienkova V, Peter MF, Rheinberger J, Paulino C. Nature 623 202-209 (2023)
  6. Alkali metal cations modulate the geometry of different binding sites in HCN4 selectivity filter for permeation or block. Krumbach JH, Bauer D, Sharifzadeh AS, Saponaro A, Lautenschläger R, Lange K, Rauh O, DiFrancesco D, Moroni A, Thiel G, Hamacher K. J Gen Physiol 155 e202313364 (2023)
  7. Cryo-EM structure of human HCN3 channel and its regulation by cAMP. Yu B, Lu Q, Li J, Cheng X, Hu H, Li Y, Che T, Hua Y, Jiang H, Zhang Y, Xian C, Yang T, Fu Y, Chen Y, Nan W, McCormick PJ, Xiong B, Duan J, Zeng B, Li Y, Fu Y, Zhang J. J Biol Chem 300 107288 (2024)
  8. Structural basis for hyperpolarization-dependent opening of human HCN1 channel. Burtscher V, Mount J, Huang J, Cowgill J, Chang Y, Bickel K, Chen J, Yuan P, Chanda B. Nat Commun 15 5216 (2024)


Reviews citing this publication (7)

  1. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  2. Paradigm shift: new concepts for HCN4 function in cardiac pacemaking. Hennis K, Biel M, Fenske S, Wahl-Schott C. Pflugers Arch 474 649-663 (2022)
  3. Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents. Wu SN, Wu CL, Cho HY, Chiang CW. Int J Mol Sci 23 9453 (2022)
  4. Detergents and alternatives in cryo-EM studies of membrane proteins. Li S. Acta Biochim Biophys Sin (Shanghai) 54 1049-1056 (2022)
  5. Structural basis of properties, mechanisms, and channelopathy of cyclic nucleotide-gated channels. Hu Z, Yang J. Channels (Austin) 17 2273165 (2023)
  6. Structural Plasticity of the Selectivity Filter in Cation Channels. Hendriks K, Öster C, Lange A. Front Physiol 12 792958 (2021)
  7. The Dysfunction of Ca2+ Channels in Hereditary and Chronic Human Heart Diseases and Experimental Animal Models. Shemarova I. Int J Mol Sci 24 15682 (2023)

Articles citing this publication (17)

  1. Anionic lipids unlock the gates of select ion channels in the pacemaker family. Schmidpeter PAM, Wu D, Rheinberger J, Riegelhaupt PM, Tang H, Robinson CV, Nimigean CM. Nat Struct Mol Biol 29 1092-1100 (2022)
  2. Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. Merseburg A, Kasemir J, Buss EW, Leroy F, Bock T, Porro A, Barnett A, Tröder SE, Engeland B, Stockebrand M, Moroni A, Siegelbaum SA, Isbrandt D, Santoro B. Elife 11 e70826 (2022)
  3. Computational Prediction of Phosphoinositide Binding to Hyperpolarization-Activated Cyclic-Nucleotide Gated Channels. Claveras Cabezudo A, Feriel Khoualdi A, D'Avanzo N. Front Physiol 13 859087 (2022)
  4. Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel. Gao X, Schmidpeter PAM, Berka V, Durham RJ, Fan C, Jayaraman V, Nimigean CM. Nat Commun 13 6919 (2022)
  5. Ion behavior in the selectivity filter of HCN1 channels. Ahrari S, Ozturk TN, D'Avanzo N. Biophys J 121 2206-2218 (2022)
  6. Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Pan Y, Pohjolainen E, Schmidpeter PAM, Vaiana AC, Nimigean CM, Grubmüller H, Scheuring S. Nat Struct Mol Biol 30 512-520 (2023)
  7. A high affinity switch for cAMP in the HCN pacemaker channels. Porro A, Saponaro A, Castelli R, Introini B, Hafez Alkotob A, Ranjbari G, Enke U, Kusch J, Benndorf K, Santoro B, DiFrancesco D, Thiel G, Moroni A. Nat Commun 15 843 (2024)
  8. Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel. Ng LCT, Li YX, Van Petegem F, Accili EA. Biophys J 121 1166-1183 (2022)
  9. When Is a Potassium Channel Not a Potassium Channel? Accili E. Function (Oxf) 3 zqac052 (2022)
  10. cAMP binding to closed pacemaker ion channels is cooperative. Kuschke S, Thon S, Sattler C, Schwabe T, Benndorf K, Schmauder R. Proc Natl Acad Sci U S A 121 e2315132121 (2024)
  11. A Novel Flow Cytometry-Based Assay for the Identification of HCN4 CNBD Ligands. Wojciechowski MN, Schreiber S, Jose J. Pharmaceuticals (Basel) 16 710 (2023)
  12. Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels. Page DA, Ruben PC. J Gen Physiol 156 e202313505 (2024)
  13. LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction. Peters CH, Singh RK, Langley AA, Nichols WG, Ferris HR, Jeffrey DA, Proenza C, Bankston JR. Elife 12 RP92411 (2024)
  14. Loose Coupling between the Voltage Sensor and the Activation Gate in Mammalian HCN Channels Suggests a Gating Mechanism. Wu X, Cunningham KP, Bruening-Wright A, Pandey S, Larsson HP. Int J Mol Sci 25 4309 (2024)
  15. Palmitoylation regulates the magnitude of HCN4-mediated currents in mammalian cells. Congreve SD, Main A, Butler AS, Gao X, Brown E, Du C, Choisy SC, Cheng H, Hancox JC, Fuller W. Front Physiol 14 1163339 (2023)
  16. Two HCN4 Channels Play Functional Roles in the Zebrafish Heart. Liu J, Kasuya G, Zempo B, Nakajo K. Front Physiol 13 901571 (2022)
  17. Validation of the binding stoichiometry between HCN channels and their neuronal regulator TRIP8b by single molecule measurements. Saponaro A, Vallese F, Porro A, Clarke OB. Front Physiol 13 998176 (2022)


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