Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits
Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits
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DOI：
10.1074/jbc.274.30.21063
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发表时间：
1999-07-23
影响因子：
4.8
通讯作者：
Sanguinetti, MC
中科院分区：
文献类型：
--
作者：
Franqueza, L;Lin, M;Sanguinetti, MC
长 QT 综合征是一种遗传性心脏复极疾病，由心脏离子通道基因（包括 KVLQT1）突变引起。在这项研究中，利用非洲爪蟾卵母细胞异源表达系统和两微电极电压钳技术来表征 KVLQT1 中三个长 QT 相关错义突变（R243C、W248R、E261K）的功能后果。这些突变位于 S4 和 S5 跨膜结构域之间的细胞内连接子中或附近，该区域与钾通道的激活门控有关。 E261K突变导致功能丧失，不与野生型KvLQT1亚基相互作用，R243C或W248R KVLQT1亚基形成功能通道，但与野生型KVLQT1电流相比，激活速率更慢，激活和失活的电压依赖性转向更正的电位。 minK 和 KvLQT1 通道亚基的共同表达会诱导缓慢的延迟整流 K+ 电流 I-Ks，其特征是与 KVLQT1 亚基单独诱导的电流相比，激活缓慢且幅度显着增加。 minK 与 R243C 或 W248R KvLQT1 亚基的共表达抑制了电流，表明突变亚基与 minK 的共组装阻止了正常的通道门控。功能丧失或门控特性改变引起的 I-K 下降解释了与 KVLQT1 突变相关的 QT 间期延长以及心律失常和猝死风险增加。
Long QT syndrome is an inherited disorder of cardiac repolarization caused by mutations in cardiac ion channel genes, including KVLQT1. In this study, the functional consequences of three long QT-associated missense mutations in KVLQT1 (R243C, W248R, E261K) were characterized using the Xenopus oocyte heterologous expression system and two-microelectrode voltage clamp techniques. These mutations are located in or near the intracellular linker between the S4 and S5 transmembrane domains, a region implicated in activation gating of potassium channels. The E261K mutation caused loss of function and did not interact with wildtype KvLQT1 subunits, R243C or W248R KVLQT1 subunits formed functional channels, but compared with wild-type KVLQT1 current, the rate of activation was slower, and the voltage dependence of activation and inactivation was shifted to more positive potentials. Co expression of minK and KvLQT1 channel subunits induces a slow delayed rectifier K+ current, I-Ks, characterized by slow activation and a markedly increased magnitude compared with current induced by KVLQT1 subunits alone. Coexpression of minK with R243C or W248R KvLQT1 subunits suppressed current, suggesting that coassembly of mutant subunits with minK prevented normal channel gating. The decrease in I-Ks caused by loss of function or altered gating properties explains the prolonged QT interval and increased risk of arrhythmia and sudden death associated with these mutations in KVLQT1.