2. Academic Validation
  3. Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness

Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness

  • Nat Chem Biol. 2014 Jun;10(6):457-62. doi: 10.1038/nchembio.1521.
Marco Lolicato 1,  Annalisa Bucchi 1,  Cristina Arrigoni 2,  Stefano Zucca 2,  Marco Nardini 2,  Indra Schroeder 3,  Katie Simmons 4,  Marco Aquila 2,  Dario DiFrancesco 2,  Martino Bolognesi 5,  Frank Schwede 6,  Dmitry Kashin 6,  Colin W G Fishwick 4,  A Peter Johnson 4,  Gerhard Thiel 3,  Anna Moroni 5
Affiliations

Affiliations

  • 1 1] Department of Biosciences, University of Milan, Milan, Italy. [2].
  • 2 Department of Biosciences, University of Milan, Milan, Italy.
  • 3 Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.
  • 4 School of Chemistry, University of Leeds, Leeds, UK.
  • 5 1] Department of Biosciences, University of Milan, Milan, Italy. [2] Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Milan, Italy.
  • 6 BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH D-28199, Bremen, Germany.
PMID: 24776929 DOI: 10.1038/nchembio.1521
Abstract

cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder β-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system.

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