A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel
A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel
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负责心脏钾通道表面表达的疏水性依赖性基序。
DOI：
10.1016/j.cellsig.2008.11.006
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发表时间：
2009-02-01
影响因子：
4.8
通讯作者：
Ding, Jiuping
中科院分区：
文献类型：
--
作者：
Pan, Na;Sun, Jing;Ding, Jiuping
长qt综合征（LQTS）是一种与晕厥和猝死高风险相关的遗传性心脏疾病。1型LQTS （LQT1）的分子基础是KCNQ通道的错义或无义突变，该突变减少缓慢激活的延迟整流钾通道(6)，导致动作电位延长。值得注意的是，S2-S3连接子是LQT1突变的高度聚集区域。为了进一步探索这一机制，研究人员选择了在一个具有LQT1的中国家系中发现的KCNQ突变体（L191P）。由于Leu-191位于细胞内S2-S3连接体中一个众所周知的内质网定位信号（RXR）的中间，我们研究了KCNQ1和L191突变体的动力学和表面表达。我们的研究结果表明，突变不影响通道动力学，而表面表达随着RXR基序中间残基X疏水性的增加而增加。基于二项模型对分数荧光数据的分析，我们还发现，在KCNQ1: L191P = 1:1的转染比例下，细胞表面表达的KCNQ1/L191P异质通道的比例分别为22.0%、40.5%、27.9%、8.6%和1.0%，分别含有L191P的0、1、2、3和4个亚基。这些实验表明，L191P的共表达导致转运因子α < 1，导致异质通道的转运不足，这是显性负作用的基础。该研究表明，该地区存在多种贩运信号，并扩大了我们对LQTS可能的显性-负性机制的理解。(c) 2008爱思唯尔公司版权所有。
The long-QT syndrome (LQTS) is an inherited cardiac disorder associated with syncope and a high risk of sudden death. The molecular basis of type-1 LQTS (LQT1) is a missense or nonsense mutation in KCNQ channels that reduces slowly activating delayed rectifier potassium channel (6) resulting in a prolonged action potential. Noticeably, the S2-S3 linker is a highly congregating region of LQT1 mutations. To further explore the mechanism, a KCNQ mutant (L191P) identified in one Chinese pedigree with LQT1 was chosen for this purpose. As Leu-191 is located in the middle of a well-known endoplasmic reticulum (ER) localization signal (RXR) in the intracellular S2-S3 linker, we examined the kinetics and the surface expression of both the KCNQ1 and L191 mutants. Our results showed that the mutation did not affect the channel kinetics, whereas the surface expression increased with increasing hydrophobicity of the middle residue X of the RXR motif. Based on an analysis of fractional fluorescence data using a binomial model, we also found that the percentage of KCNQ1/L191P heteromeric channels expressed at the cell surface were 22.0%, 40.5%, 27.9%, 8.6% and 1.0% of heteromeric channels with 0, 1, 2, 3 and 4 subunits of L191 P, respectively, in a transfected ratio of KCNQ1: L191P = 1:1. These experiments demonstrated that coexpression of L191P resulted in a trafficking factor alpha < 1, causing a trafficking deficiency of heteromeric channels that underlay the dominant-negative effect. This study suggests several trafficking signals coexisting in this region, and expands our understanding of possible dominant-negative mechanisms underlying LQTS. (c) 2008 Elsevier Inc. All rights reserved.