Lolicato, Marco ; Bucchi, Annalisa ; Arrigoni, Cristina ; Zucca, Stefano ; Nardini, Marco ; Schroeder, Indra ; Simmons, Katie ; Aquila, Marco ; DiFrancesco, Dario ; Bolognesi, Martino ; Schwede, Frank ; Kashin, Dmitry ; Fishwick, Colin W. G. ; Johnson, A. Peter ; Thiel, Gerhard ; Moroni, Anna (2014)
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
In: Nature chemical biology, 10 (6)
doi: 10.1038/nchembio.1521
Artikel, Bibliographie
Kurzbeschreibung (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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2014 |
| Autor(en): | Lolicato, Marco ; Bucchi, Annalisa ; Arrigoni, Cristina ; Zucca, Stefano ; Nardini, Marco ; Schroeder, Indra ; Simmons, Katie ; Aquila, Marco ; DiFrancesco, Dario ; Bolognesi, Martino ; Schwede, Frank ; Kashin, Dmitry ; Fishwick, Colin W. G. ; Johnson, A. Peter ; Thiel, Gerhard ; Moroni, Anna |
| Art des Eintrags: | Bibliographie |
| Titel: | Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness |
| Sprache: | Englisch |
| Publikationsjahr: | 28 April 2014 |
| Verlag: | Nature Publishing Group |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Nature chemical biology |
| Jahrgang/Volume einer Zeitschrift: | 10 |
| (Heft-)Nummer: | 6 |
| DOI: | 10.1038/nchembio.1521 |
| Kurzbeschreibung (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. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Plant Membrane Biophyscis (am 20.12.23 umbenannt in Biologie der Algen und Protozoen) |
| Hinterlegungsdatum: | 06 Mai 2014 09:05 |
| Letzte Änderung: | 29 Nov 2021 12:41 |
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