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KCNH2 突变体的功能研究：LQT2 综合征发病机制的新见解。

Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

机构信息

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.

Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

出版信息

J Cell Mol Med. 2019 Sep;23(9):6331-6342. doi: 10.1111/jcmm.14521. Epub 2019 Jul 30.

DOI:10.1111/jcmm.14521
PMID:31361068
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6714209/
Abstract

The K voltage-gated channel subfamily H member 2 (KCNH2) transports the rapid component of the cardiac delayed rectifying K current. The aim of this study was to characterize the biophysical properties of a C-terminus-truncated KCNH2 channel, G1006fs/49 causing long QT syndrome type II in heterozygous members of an Italian family. Mutant carriers underwent clinical workup, including 12-lead electrocardiogram, transthoracic echocardiography and 24-hour ECG recording. Electrophysiological experiments compared the biophysical properties of G1006fs/49 with those of KCNH2 both expressed either as homotetramers or as heterotetramers in HEK293 cells. Major findings of this work are as follows: (a) G1006fs/49 is functional at the plasma membrane even when co-expressed with KCNH2, (b) G1006fs/49 exerts a dominant-negative effect on KCNH2 conferring specific biophysical properties to the heterotetrameric channel such as a significant delay in the voltage-sensitive transition to the open state, faster kinetics of both inactivation and recovery from the inactivation and (c) the activation kinetics of the G1006fs/49 heterotetrameric channels is partially restored by a specific KCNH2 activator. The functional characterization of G1006fs/49 homo/heterotetramers provided crucial findings about the pathogenesis of LQTS type II in the mutant carriers, thus providing a new and potential pharmacological strategy.

摘要

K 电压门控通道亚家族 H 成员 2（KCNH2）转运快速成分的心脏延迟整流钾电流。本研究的目的是描述 C 端截断 KCNH2 通道的生物物理特性，该通道突变 G1006fs/49 导致意大利一个家族的杂合子成员出现长 QT 综合征 II 型。突变携带者接受了临床检查，包括 12 导联心电图、经胸超声心动图和 24 小时心电图记录。电生理实验比较了 G1006fs/49 与 KCNH2 的生物物理特性，KCNH2 既可以作为同源四聚体表达，也可以作为异源四聚体在 HEK293 细胞中表达。这项工作的主要发现如下：（a）G1006fs/49 即使与 KCNH2 共表达，也能在质膜上发挥功能；（b）G1006fs/49 对 KCNH2 产生显性负效应，赋予异源四聚体通道特定的生物物理特性，例如电压敏感向开放状态转变的显著延迟、失活和恢复的更快动力学；（c）G1006fs/49 异源四聚体通道的激活动力学部分被特定的 KCNH2 激活剂恢复。G1006fs/49 同源/异源四聚体的功能特征为突变携带者的 II 型长 QT 综合征的发病机制提供了关键发现，从而提供了一种新的潜在的药理学策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/9a2c7dc65450/JCMM-23-6331-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/6479470cc853/JCMM-23-6331-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/19d7786e5a91/JCMM-23-6331-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/a486f46a7671/JCMM-23-6331-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/76dd5425d3e5/JCMM-23-6331-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/9a2c7dc65450/JCMM-23-6331-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/6479470cc853/JCMM-23-6331-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/6e7ce1b88244/JCMM-23-6331-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/19d7786e5a91/JCMM-23-6331-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/ab3c520135b3/JCMM-23-6331-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/a486f46a7671/JCMM-23-6331-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/76dd5425d3e5/JCMM-23-6331-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1638/6714209/9a2c7dc65450/JCMM-23-6331-g007.jpg

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