{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium",
    "School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom",
    "Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium",
    "Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium",
    "Institut für Physiologie II, Universitätsklinikum Jena, Jena, Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Valentina Zorzini"
    },
    {
      "affs": [
        0
      ],
      "name": "Jessica Kleiz-Ferreira"
    },
    {
      "affs": [
        0
      ],
      "name": "Marijke Brams"
    },
    {
      "affs": [
        1
      ],
      "name": "Rodrigo Gallardo"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Steven De Gieter"
    },
    {
      "affs": [
        4
      ],
      "name": "Jana Kusch"
    },
    {
      "affs": [
        0
      ],
      "name": "Chris Ulens"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ehw97qz3yztrx.bib",
  "cited_by": 0,
  "doi": "10.1016/j.jbc.2026.113589",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715422/",
  "id": "ehw97qz3yztrx",
  "issns": [
    "0021-9258",
    "1083-351X"
  ],
  "landing_url": "https://doi.org/10.1016/j.jbc.2026.113589",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7214104992",
  "pdf_url": null,
  "pmcid": "PMC13715422",
  "pmid": "42772566",
  "published": "2026-09-23",
  "publisher": "American Society for Biochemistry and Molecular Biology",
  "ris": "https://research.draconitic.com/paper/ehw97qz3yztrx.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:22:43Z",
      "native_id": "PMC13715422",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.jbc.2026.113589"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ion channel regulation and function",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels",
  "title_text": "Structural basis of isoform-specific cAMP regulation and autoinhibition in hyperpolarization-activated cyclic nucleotide-gated channels",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:43Z",
  "url": "https://research.draconitic.com/paper/ehw97qz3yztrx",
  "venue": "The Journal of Biological Chemistry",
  "versions": []
}