http://www.cnr.it/ontology/cnr/individuo/prodotto/ID293267
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness (Articolo in rivista)
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- Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness (Articolo in rivista) (literal)
- Anno
- 2014-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1038/NCHEMBIO.1521 (literal)
- Alternative label
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
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- 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 (literal)
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- ISI Web of Science (WOS) (literal)
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- University of Milan; Darmstadt University of Technology; University of Leeds; Consiglio Nazionale delle Ricerche (CNR); Forschungslabor & Biochem Vertrieb GmbH (literal)
- Titolo
- Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness (literal)
- Abstract
- cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current I-f. 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 I-f in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder beta-adrenergic stimulation on I-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. (literal)
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