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 f. 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.
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness / M. Lolicato, A. Bucchi, C. Arrigoni, S. Zucca, M. Nardini, I. Schroeder, K. Simmons, M. Aquila, D. Difrancesco, M. Bolognesi, F. Schwede, D. Kashin, C.W.G. Fishwick, A.P. Johnson, G. Thiel, A. Moroni. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4450. - 10:6(2014), pp. 457-462.
|Titolo:||Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness|
LOLICATO, MARCO GAETANO LORENZO (Primo)
BUCCHI, ANNALISA (Secondo)
MORONI, ANNA (Ultimo)
|Parole Chiave:||animals; binding sites; blotting, western; crystallography, x-ray; cyclic AMP; cyclic GMP; dinucleoside phosphates; HEK293 cells; high-throughput screening assays; humans; hyperpolarization-activated cyclic nucleotide-gated channels; ion channel gating; ligands; mice; mice, inbred C57BL; molecular docking simulation; molecular structure; muscle proteins; myocytes, cardiac; patch-clamp techniques; potassium channels; sinoatrial node; small molecule libraries; transfection; cell biology; molecular biology|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/nchembio.1521|
|Appare nelle tipologie:||01 - Articolo su periodico|