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

doi:10.1074/jbc.M114.572164

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

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 language	English (US)
Pages (from-to)	22205-22220
Number of pages	16
Journal	Journal of Biological Chemistry
Volume	289
Issue number	32
DOIs	https://doi.org/10.1074/jbc.M114.572164
State	Published - Aug 8 2014

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10.1074/jbc.M114.572164

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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",

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doi = "10.1074/jbc.M114.572164",

language = "English (US)",

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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 - https://www.scopus.com/pages/publications/84905836722

UR - https://www.scopus.com/pages/publications/84905836722#tab=citedBy

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DO - 10.1074/jbc.M114.572164

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AN - SCOPUS:84905836722

SN - 0021-9258

VL - 289

SP - 22205

EP - 22220

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 32

ER -

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

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