A high affinity switch for cAMP in the HCN pacemaker channels

Alessandro Porro, Andrea Saponaro, Roberta Castelli, Bianca Introini, Anahita Hafez Alkotob, Golnaz Ranjbari, Uta Enke, Jana Kusch, Klaus Benndorf, Bina Santoro, Dario DiFrancesco, Gerhard Thiel and Anna Moroni ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45136-y

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