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

Acute stress provokes lethal cardiac arrhythmias in the hereditary long QT syndrome. Here we provide a novel molecular mechanism linking beta-adrenergic signaling and altered human ether-a-go-go related gene (HERG) channel activity. Stress stimulates beta-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 14-3-3epsilon 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.

Pubmed ID: 11953308

Authors

  • Kagan A
  • Melman YF
  • Krumerman A
  • McDonald TV

Journal

The EMBO journal

Publication Data

April 15, 2002

Associated Grants

  • Agency: AHRQ HHS, Id: R01 HS57388

Mesh Terms

  • 14-3-3 Proteins
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • CHO Cells
  • Cation Transport Proteins
  • Cell Line
  • Cricetinae
  • Cyclic AMP-Dependent Protein Kinases
  • DNA-Binding Proteins
  • Dimerization
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Receptors, Adrenergic, beta
  • Trans-Activators
  • Two-Hybrid System Techniques
  • Tyrosine 3-Monooxygenase