A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP

Madoka Akimoto, Zaiyong Zhang, Stephen Boulton, Rajeevan Selvaratnam, Bryan Van Schouwen, Melanie Gloyd, Eric A. Accili, Oliver F. Lange, Giuseppe Melacini

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Background: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control electrical activity through tetramerization of an intracellular linker. Results: NMR shows that the apo-cAMP-binding domain (CBD) of HCN4 destabilizes the tetramer through steric clashes. Conclusion: The apo-HCN4 CBD structure is compatible with monomeric and dimeric but not with tetrameric HCN4. Significance: The proposed mechanism explains HCN auto-inhibition and its relaxation by cAMP.

Original languageEnglish
Pages (from-to)22205-22220
Number of pages16
JournalJournal of Biological Chemistry
Volume289
Issue number32
DOIs
Publication statusPublished - 2014 Aug 8

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Akimoto, M., Zhang, Z., Boulton, S., Selvaratnam, R., Van Schouwen, B., Gloyd, M., Accili, E. A., Lange, O. F., & Melacini, G. (2014). A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. Journal of Biological Chemistry, 289(32), 22205-22220. https://doi.org/10.1074/jbc.M114.572164