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

The EMBO journal | Apr 15, 2002

http://www.ncbi.nlm.nih.gov/pubmed/11953308

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 RIS Download

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

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Associated grants

  • Agency: AHRQ HHS, Id: R01 HS57388

GO (Data, Gene Annotation)

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