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Pharmacological rescue of hERG currents carried out by G604S and wide type hERG co‐expression
Author(s) -
Huo Jianhua,
Zhang Aifeng,
Guo Xueyan,
Qiang Hua,
Liu Ping,
Bai Ling,
Ma Aiqun
Publication year - 2016
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12593
Subject(s) - herg , chemistry , pharmacology , safety pharmacology , protein expression , microbiology and biotechnology , biophysics , biology , biochemistry , potassium channel , gene , drug
Summary Mutations in human ether‐a‐go‐go‐related gene ( hERG ) can lead to type 2 long‐ QT syndrome ( LQT 2). The authors previously identified the hERG mutation G604S results in a loss of function and obviously decreased current amplitude and impaired channel protein trafficking when co‐expressed with WT ‐ hERG . The present study further investigates the biological and electrophysiological consequences of pharmacologic chaperones in HEK 293 cells expressing G604S‐ hERG or co‐expressing G604S‐ hERG and WT ‐ hERG . It was found that a low temperature (27°C), thapsigargin, NS 1643 and E‐4031 fail to rescue the G604S mutation. Interestingly, only E‐4031 treatment resulted in a significant increase in hERG currents in cells co‐expressing G604S‐ hERG and WT ‐ hERG , correspondingly more mature protein band at 155 kDa by Western blotting and an increased membrane staining by confocal microscopy. In addition, E‐4031 treatment shifted the steady‐state half maximal activation voltage ( V 1/2 ) of the inactivation curve by +8 mV in cells co‐expressing G604S‐ hERG and WT ‐ hERG . The present experimental results suggest that a G604S mutation is resistant to pharmacological rescue. E‐4031 treatment resulted in a significant increase in hERG currents by promoting the hERG channel processing and trafficking in cells co‐expressing G604S‐ hERG and WT‐hERG.