14-3-3 amplifies and prolongs adrenergic stimulation of HERG K+ channel activity
14-3-3 amplifies and prolongs adrenergic stimulation of HERG K+ channel activity
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DOI：
10.1093/emboj/21.8.1889
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发表时间：
2002-04-15
期刊：
影响因子：
11.4
通讯作者：
McDonald, TV
中科院分区：
文献类型：
--
作者：
Kagan, A;Melman, YF;McDonald, TV
急性应激可引起遗传性长QT综合征致死性心律失常。在这里，我们提供了一种新的分子机制，将β -肾上腺素能信号和改变的人类乙醚-a-go-go相关基因（HERG）通道活性联系起来。应激刺激β -肾上腺素能受体，导致cAMP升高，可直接或通过cAMP依赖性蛋白激酶（PKA）磷酸化调节HERG K+通道。我们发现HERG与14-3-3 -3epsilon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加速并增强了HERG的激活，这一作用需要PKA磷酸化HERG和14-3-3的二聚化。这种相互作用还通过屏蔽磷酸盐免受细胞磷酸酶的影响，稳定了通道pka磷酸化状态的寿命。最终结果是延长肾上腺素能刺激对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了一种独特的机制。
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.