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A high affinity switch for cAMP in the HCN pacemaker channels

Author

Listed:
  • Alessandro Porro

    (University of Milan)

  • Andrea Saponaro

    (University of Milan)

  • Roberta Castelli

    (University of Milan)

  • Bianca Introini

    (University of Milan)

  • Anahita Hafez Alkotob

    (University of Milan)

  • Golnaz Ranjbari

    (University of Milan)

  • Uta Enke

    (Universitätsklinikum Jena)

  • Jana Kusch

    (Universitätsklinikum Jena)

  • Klaus Benndorf

    (Universitätsklinikum Jena)

  • Bina Santoro

    (Columbia University)

  • Dario DiFrancesco

    (University of Milan)

  • Gerhard Thiel

    (TU-Darmstadt)

  • Anna Moroni

    (University of Milan
    Consiglio Nazionale delle Ricerche)

Abstract

Binding of cAMP to Hyperpolarization activated cyclic nucleotide gated (HCN) channels facilitates pore opening. It is unclear why the isolated cyclic nucleotide binding domain (CNBD) displays in vitro lower affinity for cAMP than the full-length channel in patch experiments. Here we show that HCN are endowed with an affinity switch for cAMP. Alpha helices D and E, downstream of the cyclic nucleotide binding domain (CNBD), bind to and stabilize the holo CNBD in a high affinity state. These helices increase by 30-fold cAMP efficacy and affinity measured in patch clamp and ITC, respectively. We further show that helices D and E regulate affinity by interacting with helix C of the CNBD, similarly to the regulatory protein TRIP8b. Our results uncover an intramolecular mechanism whereby changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels, adding another layer to the complex regulation of their activity.

Suggested Citation

  • Alessandro Porro & Andrea Saponaro & Roberta Castelli & Bianca Introini & Anahita Hafez Alkotob & Golnaz Ranjbari & Uta Enke & Jana Kusch & Klaus Benndorf & Bina Santoro & Dario DiFrancesco & Gerhard , 2024. "A high affinity switch for cAMP in the HCN pacemaker channels," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45136-y
    DOI: 10.1038/s41467-024-45136-y
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    References listed on IDEAS

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    1. William N. Zagotta & Nelson B. Olivier & Kevin D. Black & Edgar C. Young & Rich Olson & Eric Gouaux, 2003. "Structural basis for modulation and agonist specificity of HCN pacemaker channels," Nature, Nature, vol. 425(6954), pages 200-205, September.
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