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14‐3‐3 amplifies and prolongs adrenergic stimulation of HERG K + channel activity
Author(s) -
Kagan Anna,
Melman Yonathan F.,
Krumerman Andrew,
McDonald Thomas V.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.8.1889
Subject(s) - herg , biology , stimulation , adrenergic , pharmacology , channel (broadcasting) , neuroscience , potassium channel , endocrinology , genetics , receptor , engineering , electrical engineering
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.