Requirement of a macromolecular signaling complex for β adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel
Requirement of a macromolecular signaling complex for β adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel
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DOI：
10.1126/science.1066843
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发表时间：
2002-01-18
期刊：
影响因子：
56.9
通讯作者：
Kass, RS
中科院分区：
文献类型：
--
作者：
Marx, SO;Kurokawa, J;Kass, RS
交感神经系统(SNS)对心脏动作电位时程的调节是通过激活β-肾上腺素能受体(β-AR)来实现的，β-肾上腺素能受体(β-AR)可增加钾离子电流(I-K)。人类I-Ks通道的两个亚基hKCNQ1和hKCNE1的突变会延长时程，并导致遗传性心律失常，称为LQTS(长QT综合征)。我们发现，I-Ks的PAR调控需要通过靶向蛋白ytiao将腺苷3‘，5’-单磷酸(CAMP)依赖的蛋白激酶(PKA)和蛋白磷酸酶1(PP1)靶向hKCNQ1。该基因通过亮氨酸拉链基序与hKCNQ1结合，该基序被LQTS突变(hKCNQ1-G589D)破坏。HKCNQ1大分子复合体的鉴定为SNS通过I-Ks调控心脏动作电位提供了机制。
Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta adrenergic receptor (betaAR) activation, which increases the stow outward potassium ion current (I-Ks). Mutations in two human I-Ks channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that PAR modulation of I-Ks requires targeting of adenosine 3',5'-monophosphate (cAMP)dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through I-Ks.