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.
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
EMBO J.
Date: Apr. 15, 2002
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