title: hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.
abstract: 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.
authors.affiliation: Development Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: hisashi.nogawa@mb.kyorin-pharm.co.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nogawa
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006329:Heart Conduction System / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D004364:Pharmaceutical Preparations
keywords: Acquired long QT syndrome; Safety pharmacology; hERG channel; hERG trafficking inhibition