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

44 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
Externally publishedYes

Fingerprint

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Cyclic Nucleotides
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. / Akimoto, Madoka; Zhang, Zaiyong; Boulton, Stephen; Selvaratnam, Rajeevan; Van Schouwen, Bryan; Gloyd, Melanie; Accili, Eric A.; Lange, Oliver F.; Melacini, Giuseppe.

In: Journal of Biological Chemistry, Vol. 289, No. 32, 08.08.2014, p. 22205-22220.

Research output: Contribution to journalArticle

Akimoto, M, Zhang, Z, Boulton, S, Selvaratnam, R, Van Schouwen, B, Gloyd, M, Accili, EA, Lange, OF & 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, vol. 289, no. 32, pp. 22205-22220. https://doi.org/10.1074/jbc.M114.572164
Akimoto, Madoka ; Zhang, Zaiyong ; Boulton, Stephen ; Selvaratnam, Rajeevan ; Van Schouwen, Bryan ; Gloyd, Melanie ; Accili, Eric A. ; Lange, Oliver F. ; Melacini, Giuseppe. / A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 32. pp. 22205-22220.
@article{22a6bb7326304c839825348519ebe9b1,
title = "A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP",
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.",
author = "Madoka Akimoto and Zaiyong Zhang and Stephen Boulton and Rajeevan Selvaratnam and {Van Schouwen}, Bryan and Melanie Gloyd and Accili, {Eric A.} and Lange, {Oliver F.} and Giuseppe Melacini",
year = "2014",
month = "8",
day = "8",
doi = "10.1074/jbc.M114.572164",
language = "English",
volume = "289",
pages = "22205--22220",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "32",

}

TY - JOUR

T1 - A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP

AU - Akimoto, Madoka

AU - Zhang, Zaiyong

AU - Boulton, Stephen

AU - Selvaratnam, Rajeevan

AU - Van Schouwen, Bryan

AU - Gloyd, Melanie

AU - Accili, Eric A.

AU - Lange, Oliver F.

AU - Melacini, Giuseppe

PY - 2014/8/8

Y1 - 2014/8/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84905836722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905836722&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.572164

DO - 10.1074/jbc.M114.572164

M3 - Article

VL - 289

SP - 22205

EP - 22220

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -