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Peer-reviewedCC BY 4.0The Journal of Biological Chemistry

Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels

  • Valentina Zorzini1
  • Jessica Kleiz-Ferreira1
  • Marijke Brams1
  • Rodrigo Gallardo2
  • Steven De Gieter3,4
  • Jana Kusch5
  • Chris Ulens1
5 affiliations
  1. 1Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium
  2. 2School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
  3. 3Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
  4. 4Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
  5. 5Institut für Physiologie II, Universitätsklinikum Jena, Jena, Germany
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Abstract

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate rhythmic electrical activity in cardiac and neuronal tissues, with isoform-specific cyclic AMP (cAMP) sensitivity remaining poorly understood. While HCN2 exhibits strong cAMP regulation, HCN1 shows minimal response. To investigate the structural basis of this divergence, we analyzed two engineered HCN1 variants using cryo-electron microscopy. One variant (HCN112) incorporates the C-linker and cyclic nucleotide-binding domain from HCN2 into the HCN1 backbone and exhibited enhanced cAMP sensitivity, with structural analysis revealing a compressed cytoplasmic domain arrangement that may facilitate regulatory interactions. In contrast, the truncated HCN1ΔC variant (lacking the cytoplasmic domain) displayed an intermediately open pore conformation, supporting auto-inhibitory regulation by the cyclic nucleotide-binding domain in wild-type channels. These structural insights elucidate how domain-specific interactions modulate cAMP-dependent gating and intrinsic auto-inhibition, providing insights into questions about mechanistic divergence among HCN isoforms. Our findings not only shed new light on the structural mechanisms underlying isoform-specific cAMP sensitivity but also have implications for the development of therapeutic strategies targeting HCN channels in neurological and cardiac disorders.

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Cite

BibTeXRIS
BibTeX
@article{zorzini2026structural,
  title = {{Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels}},
  author = {Valentina Zorzini and Jessica Kleiz-Ferreira and Marijke Brams and Rodrigo Gallardo and Steven De Gieter and Jana Kusch and Chris Ulens},
  journal = {The Journal of Biological Chemistry},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jbc.2026.113589},
  url = {https://doi.org/10.1016/j.jbc.2026.113589},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels
AU  - Valentina Zorzini
AU  - Jessica Kleiz-Ferreira
AU  - Marijke Brams
AU  - Rodrigo Gallardo
AU  - Steven De Gieter
AU  - Jana Kusch
AU  - Chris Ulens
PY  - 2026
DA  - 2026/09/23
JO  - The Journal of Biological Chemistry
DO  - 10.1016/j.jbc.2026.113589
UR  - https://doi.org/10.1016/j.jbc.2026.113589
AB  - Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate rhythmic electrical activity in cardiac and neuronal tissues, with isoform-specific cyclic AMP (cAMP) sensitivity remaining poorly understood. While HCN2 exhibits strong cAMP regulation, HCN1 shows minimal response. To investigate the structural basis of this divergence, we analyzed two engineered HCN1 variants using cryo-electron microscopy. One variant (HCN112) incorporates the C-linker and cyclic nucleotide-binding domain from HCN2 into the HCN1 backbone and exhibited enhanced cAMP sensitivity, with structural analysis revealing a compressed cytoplasmic domain arrangement that may facilitate regulatory interactions. In contrast, the truncated HCN1ΔC variant (lacking the cytoplasmic domain) displayed an intermediately open pore conformation, supporting auto-inhibitory regulation by the cyclic nucleotide-binding domain in wild-type channels. These structural insights elucidate how domain-specific interactions modulate cAMP-dependent gating and intrinsic auto-inhibition, providing insights into questions about mechanistic divergence among HCN isoforms. Our findings not only shed new light on the structural mechanisms underlying isoform-specific cAMP sensitivity but also have implications for the development of therapeutic strategies targeting HCN channels in neurological and cardiac disorders.
SN  - 0021-9258
SN  - 1083-351X
ER  -