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

Lolicato, M.; Bucchi, A.; Arrigoni, C.; Zucca, S.; Nardini, M.; Schroeder, I.; Simmons, K.; Aquila, M.; Difrancesco, D.; Bolognesi, M.; Schwede, F.; Kashin, D.; Fishwick, C.W.G.; Johnson, A.P.; Thiel, G.; Moroni, A.

doi:10.1038/nchembio.1521

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
Autori:	LOLICATO, MARCO GAETANO LORENZO (Primo) BUCCHI, ANNALISA (Secondo) ARRIGONI, CRISTINA S. Zucca NARDINI, MARCO SCHROEDER, INDRA K. Simmons AQUILA, MARCO DI FRANCESCO, DARIO BOLOGNESI, MARTINO F. Schwede D. Kashin C. W. G. Fishwick A. P. Johnson G. Thiel MORONI, ANNA (Ultimo) mostra contributor esterni nascondi contributor esterni
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
Rivista:	NATURE CHEMICAL BIOLOGY
Tipologia:	Article (author)
Digital Object Identifier (DOI):	http://dx.doi.org/10.1038/nchembio.1521
Appare nelle tipologie:	01 - Articolo su periodico

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