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

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), pp. 457-462. Nature Publishing Group, ISSN 1552-4469,
DOI: 10.1038/nchembio.1521,
[Article]

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.

Item Type: Article
Erschienen: 2014
Creators: 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
Title: Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness
Language: English
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.

Journal or Publication Title: Nature chemical biology
Journal volume: 10
Number: 6
Publisher: Nature Publishing Group
Divisions: 10 Department of Biology
10 Department of Biology > Plant Membrane Biophysics
Date Deposited: 06 May 2014 09:05
DOI: 10.1038/nchembio.1521
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