Referenced in: none

Automatically associated channels: HCN3 , HCN4

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

Authors: Marco Lolicato, Annalisa Bucchi, Cristina Arrigoni, Stefano Zucca, Marco Nardini, Indra Schroeder, Katie Simmons, Marco Aquila, Dario DiFrancesco, Martino Bolognesi, Frank Schwede, Dmitry Kashin, Colin W G Fishwick, A Peter Johnson, Gerhard Thiel, Anna Moroni

Journal, date & volume: Nat. Chem. Biol., 2014 Jun , 10, 457-62

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24776929

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.