Regulation of deactivation by an amino terminal domain in human ether-à-go-go-related gene potassium channels.
Regulation of deactivation by an amino terminal domain in human ether-à-go-go-related gene potassium channels.
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DOI：
10.1085/jgp.112.5.637
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发表时间：
1998-11
期刊：
影响因子：
--
通讯作者：
Robertson GA
中科院分区：
文献类型：
--
作者：
Wang J;Trudeau MC;Zappia AM;Robertson GA
心室动作电位复极异常可导致与长QT综合征相关的危及生命的心律失常。复极化过程取决于由人醚-à-go-go-related基因（HERG）编码的钾通道的门控特性，特别是那些控制失活恢复速率和失活速率的通道。先前的研究表明，NH2末端的缺失增加了失活率，但在野生型通道中，NH2末端调控失活的机制尚未阐明。我们测试了HERG NH2末端通过类似于震动通道中n型失活的机制减慢失活的假设，在那里它结合到孔的内部口并阻止通道关闭。我们发现HERG对NH2末端失活的调控与Shaker n型失活在三个方面有相似之处：(a) NH2末端的缺失减缓了c型失活；(b) NH2末端的作用对外部K+浓度的升高很敏感，就好像它沿着渗透途径的结合被K+内流破坏了；(c) N-乙基马酰亚胺，共价连接到在S4-S5连接体中引入的表型半胱氨酸，模拟N缺失表型，好像NH2端与其受体位点的结合被阻碍了。然而，与Shaker中的n型失活相比，没有迹象表明NH2端阻断了HERG孔。此外，我们发现NH2末端内的单独结构域介导了失活的减慢和c型失活的促进。这些结果表明，NH2末端稳定了开放状态，并通过另一种机制促进了c型失活。
Abnormalities in repolarization of the cardiac ventricular action potential can lead to life-threatening arrhythmias associated with long QT syndrome. The repolarization process depends upon the gating properties of potassium channels encoded by the human ether-à-go-go–related gene (HERG), especially those governing the rate of recovery from inactivation and the rate of deactivation. Previous studies have demonstrated that deletion of the NH2 terminus increases the deactivation rate, but the mechanism by which the NH2 terminus regulates deactivation in wild-type channels has not been elucidated. We tested the hypothesis that the HERG NH2 terminus slows deactivation by a mechanism similar to N-type inactivation in Shaker channels, where it binds to the internal mouth of the pore and prevents channel closure. We found that the regulation of deactivation by the HERG NH2 terminus bears similarity to Shaker N-type inactivation in three respects: (a) deletion of the NH2 terminus slows C-type inactivation; (b) the action of the NH2 terminus is sensitive to elevated concentrations of external K+, as if its binding along the permeation pathway is disrupted by K+ influx; and (c) N-ethylmaleimide, covalently linked to an aphenotypic cysteine introduced within the S4–S5 linker, mimics the N deletion phenotype, as if the binding of the NH2 terminus to its receptor site were hindered. In contrast to N-type inactivation in Shaker, however, there was no indication that the NH2 terminus blocks the HERG pore. In addition, we discovered that separate domains within the NH2 terminus mediate the slowing of deactivation and the promotion of C-type inactivation. These results suggest that the NH2 terminus stabilizes the open state and, by a separate mechanism, promotes C-type inactivation.
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DOI：
10.1085/jgp.58.4.413
发表时间：
1971-10
期刊：
The Journal of general physiology
影响因子：
--
作者：
Armstrong CM
通讯作者：
Armstrong CM
影响因子：
3.8
作者：
ARMSTRONG, CM
通讯作者：
ARMSTRONG, CM
影响因子：
64.8
作者：
Roeper, J;Sewing, S;Pongs, O
通讯作者：
Pongs, O
影响因子：
56.9
作者：
HOSHI, T;ZAGOTTA, WN;ALDRICH, RW
通讯作者：
ALDRICH, RW
影响因子：
5.5
作者：
Schonherr, R;Heinemann, SH
通讯作者：
Heinemann, SH