title: Pharmacological rescue of hERG currents carried out by G604S and wide type hERG co-expression.
abstract: Mutations in human ether-a-go-go-related gene (hERG) can lead to type 2 long-QT syndrome (LQT2). 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 HEK293 cells expressing G604S-hERG or co-expressing G604S-hERG and WT-hERG. It was found that a low temperature (27°C), thapsigargin, NS1643 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 (V1/2 ) 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.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Huo
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, China.
authors.forename: Aifeng
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Shaanxi Provincial People's Hospital, Shaanxi, China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Qiang
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China.
authors.forename: Aiqun
authors.initials: A
authors.lastname: Ma
mesh_terms: D019943:Amino Acid Substitution; D003408:Cresols / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects* / Q000235:genetics*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013696:Temperature
chemical_list: D003408:Cresols; D051638:Ether-A-Go-Go Potassium Channels; D010671:Phenylurea Compounds; D010880:Piperidines; D011725:Pyridines; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; C063968:E 4031
keywords: G604S; hERG mutation; long QT syndrome; patch-clamp