Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects
Abstract
Kai-ping ZHANG1, 2, Bao-feng YANG1, 2, Bao-xin LI1, 2, *
1Department of Pharmacology, Harbin Medical University, Harbin, China; 2The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China (Key Laboratory of Cardiovascular Research, Ministry of Education), China
The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.
Keywords: potassium channel; human ether-à-go-go related gene (hERG); long QT syndrome (LQTS); activator; blocker; siRNA; biogenesis; protein trafficking
This work was supported by grants from the National Natural Science Foundation of China (No 31173050 and 30973530) and the Key Program of the National Natural Science Foundation of China (No 81230081)
* To whom correspondence should be addressed.
E-mail libx64@hotmail.com
Received 2014-05-14 Accepted 2014-08-20
Keywords:
1Department of Pharmacology, Harbin Medical University, Harbin, China; 2The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China (Key Laboratory of Cardiovascular Research, Ministry of Education), China
The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.
Keywords: potassium channel; human ether-à-go-go related gene (hERG); long QT syndrome (LQTS); activator; blocker; siRNA; biogenesis; protein trafficking
This work was supported by grants from the National Natural Science Foundation of China (No 31173050 and 30973530) and the Key Program of the National Natural Science Foundation of China (No 81230081)
* To whom correspondence should be addressed.
E-mail libx64@hotmail.com
Received 2014-05-14 Accepted 2014-08-20