Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness (Articolo in rivista)

Type
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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)
Pagina inizio
  • 457 (literal)
Pagina fine
  • 462 (literal)
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  • 10 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 6 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 6 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 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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