14-3-3 Amplifies and prolongs adrenergic stimulation of HERG K+ channel activity

Anna Kagan, Yonathan F. Melman, Andrew Krumerman, Thomas V. McDonald

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Acute stress provokes lethal cardiac arrhythmias in the hereditary long QT syndrome. Here we provide a novel molecular mechanism linking β-adrenergic signaling and altered human ether-a-go-go related gene (HERG) channel activity. Stress stimulates β-adrenergic receptors, leading to cAMP elevations that can regulate HERG K+ channels both directly and via phosphorylation by cAMP-dependent protein kinase (PKA). We show that HERG associates with 14-3-3ε to potentiate cAMP/PKA effects upon HERG. The binding of 14-3-3 occurs simultaneously at the N- and C-termini of the HERG channel. 14-3-3 accelerates and enhances HERG activation, an effect that requires PKA phosphorylation of HERG and dimerization of 14-3-3. The interaction also stabilizes the lifetime of the PKA-phosphorylated state of the channel by shielding the phosphates from cellular phosphatases. The net result is a prolongation of the effect of adrenergic stimulation upon HERG activity. Thus, 14-3-3 interactions with HERG may provide a unique mechanism for plasticity in the control of membrane excitability and cardiac rhythm.

Original languageEnglish (US)
Pages (from-to)1889-1898
Number of pages10
JournalEMBO Journal
Volume21
Issue number8
DOIs
Publication statusPublished - Apr 15 2002

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Keywords

  • 14-3-3
  • HERG
  • PKA
  • Potassium channel
  • cAMP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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