hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia
Autor: | Hisashi Nogawa, Tomoyuki Kawai |
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Rok vydání: | 2014 |
Předmět: |
congenital
hereditary and neonatal diseases and abnormalities ERG1 Potassium Channel hERG Pharmacology Protein degradation QT interval Cardiac Conduction System Disease Heart Conduction System Medicine Animals Humans cardiovascular diseases Brugada Syndrome biology business.industry Cardiac arrhythmia Cardiac action potential Arrhythmias Cardiac Potassium channel Ether-A-Go-Go Potassium Channels Protein Transport Drug development Pharmaceutical Preparations biology.protein business Anti-Arrhythmia Agents |
Zdroj: | European journal of pharmacology. 741 |
ISSN: | 1879-0712 |
Popis: | Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. |
Databáze: | OpenAIRE |
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