Kagan Anna, Melman Yonathan F, Krumerman Andrew, McDonald Thomas V
Section of Molecular Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
EMBO J. 2002 Apr 15;21(8):1889-98. doi: 10.1093/emboj/21.8.1889.
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.
急性应激可在遗传性长QT综合征中诱发致命性心律失常。在此，我们提供了一种将β-肾上腺素能信号传导与人类醚-去极化相关基因（HERG）通道活性改变联系起来的新分子机制。应激刺激β-肾上腺素能受体，导致环磷酸腺苷（cAMP）升高，其可直接或通过依赖cAMP的蛋白激酶（PKA）磷酸化来调节HERG钾通道。我们发现HERG与14-3-3ε结合，以增强cAMP/PKA对HERG的作用。14-3-3的结合同时发生在HERG通道的N端和C端。14-3-3加速并增强HERG的激活，这一效应需要HERG的PKA磷酸化和14-3-3的二聚化。这种相互作用还通过保护磷酸基团不被细胞磷酸酶作用，稳定了通道PKA磷酸化状态的寿命。最终结果是延长了肾上腺素能刺激对HERG活性的影响。因此，14-3-3与HERG的相互作用可能为控制膜兴奋性和心律的可塑性提供一种独特机制。
