The N-linker region of hERG1a upregulates hERG1b potassium channels.
The N-linker region of hERG1a upregulates hERG1b potassium channels.
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DOI：
10.1016/j.jbc.2022.102233
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发表时间：
2022-09
影响因子：
4.8
通讯作者：
Trudeau, Matthew C.
中科院分区：
文献类型：
--
作者：
Johnson, Ashley A.;Crawford, Taylor R.;Trudeau, Matthew C.
hERG 1（human Ether-á-go-go-Related Gene 1）钾通道的主要生理作用是恢复心脏动作电位。两种亚型hERG 1a和hERG 1b在心肌细胞中联合形成钾电流IKr。hERG 1a或hERG 1b的遗传突变可导致心脏复极延长、长QT综合征和猝死性心律失常。hERG 1a亚基与hERG 1b亚基在质膜上组装并增加hERG 1b亚基的数量，但hERG 1a增加hERG 1b的机制尚不清楚。在这里，我们报告，hERG 1a的N-末端区域与hERG 1b的反式表达显着增加hERG 1b电流和增加生物素标记的hERG 1b蛋白在膜表面。当与hERG 1a N-末端区域共表达时，缺失N-末端1b结构域的hERG 1b通道的电流或生物素化蛋白没有可测量的增加，表明hERG 1b增加需要1b结构域。使用生化下拉相互作用试验和FRET杂交实验，我们检测到hERG 1a N-末端区域和hERG 1b N-末端区域之间的直接相互作用。使用工程缺失和丙氨酸诱变，我们确定了hERG 1a“N-接头”区域内216至220位的一小段氨基酸，这是hERG 1b上调所必需的。我们认为hERG 1a N-连接区和hERG 1b 1b结构域之间的直接结构相互作用增加了hERG 1b在质膜上的表达。调节hERG 1a和hERG 1b的机制可能对心脏功能至关重要，可能会被长QT综合征突变体破坏，并作为治疗的潜在靶点。
A major physiological role of hERG1 (human Ether-á-go-go-Related Gene 1) potassium channels is to repolarize cardiac action potentials. Two isoforms, hERG1a and hERG1b, associate to form the potassium current IKr in cardiomyocytes. Inherited mutations in hERG1a or hERG1b cause prolonged cardiac repolarization, long QT syndrome, and sudden death arrhythmia. hERG1a subunits assemble with and enhance the number of hERG1b subunits at the plasma membrane, but the mechanism for the increase in hERG1b by hERG1a is not well understood. Here, we report that the hERG1a N-terminal region expressed in trans with hERG1b markedly increased hERG1b currents and increased biotin-labeled hERG1b protein at the membrane surface. hERG1b channels with a deletion of the N-terminal 1b domain did not have a measurable increase in current or biotinylated protein when coexpressed with hERG1a N-terminal regions, indicating that the 1b domain was required for the increase in hERG1b. Using a biochemical pull-down interaction assay and a FRET hybridization experiment, we detected a direct interaction between the hERG1a N-terminal region and the hERG1b N-terminal region. Using engineered deletions and alanine mutagenesis, we identified a short span of amino acids at positions 216 to 220 within the hERG1a “N-linker” region that were necessary for the upregulation of hERG1b. We propose that direct structural interactions between the hERG1a N-linker region and the hERG1b 1b domain increase hERG1b at the plasma membrane. Mechanisms regulating hERG1a and hERG1b are likely critical for cardiac function, may be disrupted by long QT syndrome mutants, and serve as potential targets for therapeutics.
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影响因子：
3.4
作者：
Zhou, ZF;Gong, QM;January, CT
通讯作者：
January, CT
影响因子：
64.5
作者：
Wang W;MacKinnon R
通讯作者：
MacKinnon R
影响因子：
64.5
作者：
Cabral, JHM;Lee, A;Mackinnon, R
通讯作者：
Mackinnon, R
DOI：
10.1085/jgp.201010582
发表时间：
2011-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Gustina AS;Trudeau MC
通讯作者：
Trudeau MC
影响因子：
3.8
作者：
Trudeau, Matthew C.;Leung, Lisa M.;Robertson, Gail A.
通讯作者：
Robertson, Gail A.