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

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

Research output: Contribution to journalArticle

104 Citations (Scopus)

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
StatePublished - Apr 15 2002

Fingerprint

Ether
Adrenergic Agents
Genes
Protein Kinases
Phosphorylation
Long QT Syndrome
Dimerization
Cyclic AMP-Dependent Protein Kinases
Phosphoric Monoester Hydrolases
Shielding
Adrenergic Receptors
Transcriptional Activation
Plasticity
Cardiac Arrhythmias
Chemical activation
Phosphates
Membranes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

14-3-3 Amplifies and prolongs adrenergic stimulation of HERG K+ channel activity. / Kagan, Anna; Melman, Yonathan F.; Krumerman, Andrew K.; McDonald, Thomas V.

In: EMBO Journal, Vol. 21, No. 8, 15.04.2002, p. 1889-1898.

Research output: Contribution to journalArticle

Kagan, Anna ; Melman, Yonathan F. ; Krumerman, Andrew K. ; McDonald, Thomas V. / 14-3-3 Amplifies and prolongs adrenergic stimulation of HERG K+ channel activity. In: EMBO Journal. 2002 ; Vol. 21, No. 8. pp. 1889-1898.
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